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1. Characterization of a functional V1B vasopressin receptor in the male rat kidney: evidence for cross talk between V1B and V2 receptor signaling pathways

Author: Claudine Serradeil-Le Gal, Maithé Corbani, Catherine Llorens-Cortes, Nadine Bouby, Annette Hus-Citharel, Csaba Tömböly, Christiane Mendre, Miguel Trueba, Gilles Guillon, Judit Darusi, Julie Mion, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Biological Research Center [Hungarian Academy of Sciences], University of the Basque Country [Bizkaia] (UPV/EHU), VibioSphen, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hungarian Academy of Sciences (MTA), and University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)
Subjects: 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Rat kidney, Diuresis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Vasopressin V1B and V2 receptor, 03 medical and health sciences, 0302 clinical medicine, Arginine vasopressin receptor 2, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptor, receptor heterodimerization, Arginine vasopressin receptor 1B, Messenger RNA, Kidney, Chemistry, vasopressin V1B and V2 receptors, inner medullary collecting duct, calcium and cAMP signaling, Cell biology, diuresis, 030104 developmental biology, medicine.anatomical_structure, Signal transduction
Abstract: International audience; Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2+ concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2+ mobilization and extracellular Ca2+ influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.NEW & NOTEWORTHY Although V1BR mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of V1BR, highlights a cross talk between V1BR and V2 receptor (V2R) in the inner medullary collecting duct, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation.
Published: 2021

2. QGC606: A Best-in-Class Orally Active Centrally Acting Aminopeptidase A Inhibitor Prodrug for Treating Heart Failure Following Myocardial Infarction

Author: Solène E. Boitard, Mathilde Keck, Robin Deloux, Pierre-Emmanuel Girault-Sotias, Yannick Marc, Nadia De Mota, Delphine Compere, Onnik Agbulut, Fabrice Balavoine, Catherine Llorens-Cortes, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Quantum Genomics [Paris, France] (QG), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Keck, Mathilde
Subjects: Heart Failure, Male, Ventricular Remodeling, Myocardium, [SDV]Life Sciences [q-bio], Myocardial Infarction, Glutamyl Aminopeptidase, Fibrosis, [SDV] Life Sciences [q-bio], Mice, Ramipril, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Animals, Humans, Prodrugs, RNA, Messenger, Cardiology and Cardiovascular Medicine
Abstract: International audience; Background: Blockade of brain renin-angiotensin system (RAS) overactivity by firibastat, the first centrally acting aminopeptidase A (APA) inhibitor prodrug, has already demonstrated its effectiveness in improving cardiac function after myocardial infarction (MI). We developed QGC606, a more potent and more selective APA inhibitor prodrug and studied its effects after long-term oral administration in mice post-MI.Methods: Two days after MI induced by the left anterior descending artery ligation, adult male mice were randomized into 4 groups to receive oral treatment during 4 weeks with vehicle; QGC606; firibastat; or the angiotensin-I converting enzyme inhibitor ramipril, used as positive control.Results: Four weeks post-MI, brain APA was overactivated in vehicle-treated MI mice. QGC606 treatment normalized brain APA hyperactivity to control values measured in sham-operated mice. Four weeks post-MI, QGC606-treated mice had higher left ventricular (LV) ejection fractions, significantly smaller LV end-systolic diameter and volume, significantly lower HF biomarkers mRNA expression (Myh7 and Anf) and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) and noradrenaline levels than saline-treated mice. QGC606 treatment significantly improved the dP/dt max and min, LV end-diastolic pressure without affecting blood pressure (BP), whereas we observed a decrease in BP in ramipril-treated mice. We observed also a reduction of cardiac fibrosis, highlighted by lower connective tissue growth factor mRNA levels and a reduction of both the fibrotic area and MI size in QGC606-treated mice.Conclusions: Chronic oral QGC606 administration in post-MI mice showed beneficial effects in improving cardiac function and reducing cardiac remodeling and fibrosis but, unlike ramipril, without lowering BP.
Published: 2022

3. LIT01-196, a Metabolically Stable Apelin-17 Analog, Normalizes Blood Pressure in Hypertensive DOCA-Salt Rats via a NO Synthase-dependent Mechanism

Author: Flahault, Adrien, Keck, Mathilde, Girault-Sotias, Pierre-Emmanuel, Esteoulle, Lucie, De Mota, Nadia, Bonnet, Dominique, Llorens-Cortes, Catherine, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Keck, Mathilde, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)
Subjects: [SDV]Life Sciences [q-bio], metabolically stable apelin analogs, RM1-950, DOCA-salt hypertensive rats, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, APJ, Hypertension, APJ receptor, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Apelin, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Therapeutics. Pharmacology, Metabolically stable apelin analog, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], DOCA-salt rat
Abstract: International audience; Apelin is a neuro-vasoactive peptide that plays a major role in the control of cardiovascular functions and water balance, but has an in-vivo half-life in the minute range, limiting its therapeutic use. We previously developed LIT01-196, a systemically active metabolically stable apelin-17 analog, produced by chemical addition of a fluorocarbon chain to the N-terminal part of apelin-17. LIT01-196 behaves as a potent full agonist for the apelin receptor and has an in vivo half-life in the bloodstream of 28 min after intravenous (i.v.) and 156 min after subcutaneous (s.c.) administrations in conscious normotensive rats. We aimed to investigate the effects of LIT01-196 following systemic administrations on arterial blood pressure, heart rate, fluid balance and electrolytes in conscious normotensive and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. Acute i.v. LIT01-196 administration, in increasing doses, dose-dependently decreases arterial blood pressure with ED 50 values of 9.8 and 3.1 nmol/kg in normotensive and hypertensive rats, respectively. This effect occurs for both via a nitric oxide-dependent mechanism. Moreover, acute s.c. LIT01-196 administration (90 nmol/kg) normalizes arterial blood pressure in conscious hypertensive DOCA-salt rats for more than 7 h. The LIT01-196-induced blood pressure decrease remains unchanged after 4 consecutive daily s.c. administrations of 90 nmol/kg, and does not induce any alteration of plasma sodium and potassium levels and kidney function as shown by the lack of change in plasma creatinine and urea nitrogen levels. Activating the apelin receptor with LIT01-196 may constitute a novel approach for the treatment of hypertension.
Published: 2021

4. Activating the apelin receptor with LIT01-196, a metabolically stable apelin analog, reverses AVP-induced antidiuresis and hyponatremia

Author: Flahault, Adrien, Girault-Sotias, Pierre-Emmanuel, Keck, Mathilde, Alvear-Perez, Rodrigo, De Mota, Nadia, Estéoulle, Lucie, Ramanoudjame, Sridévi, Iturrioz, Xavier, Bonnet, Dominique, Llorens-Cortes, Catherine, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Keck, Mathilde
Subjects: [SDV] Life Sciences [q-bio], [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV]Life Sciences [q-bio], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, hormones, hormone substitutes, and hormone antagonists
Abstract: International audience; Abstract Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.
Published: 2021

5. Early movement restriction leads to maladaptive plasticity in the sensorimotor cortex and to movement disorders

Author: Delcour, Maxime, Russier, Michaël, Castets, Francis, Turle-Lorenzo, Nathalie, Canu, Marie-Hélène, Cayetanot, Florence, Barbe, Mary, Coq, Jacques-Olivier, Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université de Lille-Université du Littoral Côte d'Opale (ULCO), Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Gestionnaire, Hal Sorbonne Université, Université de Montréal (UdeM), Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Institut de Neurosciences de la Timone (INT), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Neurophysiologie Respiratoire Expérimentale et Clinique, Université de Montréal [Montréal], Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Univ. Littoral Côte d’Opale, Univ. Artois, Université de Lille, Laboratoire de Neurosciences intégratives et adaptatives [LNIA], Neurobiologie des Canaux Ioniques, Centre de recherche en neurobiologie - neurophysiologie de Marseille [CRN2M], Aix Marseille Université [AMU], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS], Institut de Neurosciences de la Timone [INT], and Dpt of Anatomy and Cell Biology [Oklahoma]
Subjects: Male, Neurons, Principal Component Analysis, Movement Disorders, Neuronal Plasticity, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Developmental disorders, Neurodevelopmental disorders, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, lcsh:Medicine, Adaptation, Physiological, Article, Rats, [SDV] Life Sciences [q-bio], Hindlimb Suspension, Animals, Female, lcsh:Q, Sensorimotor Cortex, lcsh:Science, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; Motor control and body representations in the central nervous system are built, i.e., patterned, during development by sensorimotor experience and somatosensory feedback/reafference. Yet, early emergence of locomotor disorders remains a matter of debate, especially in the absence of brain damage. For instance, children with developmental coordination disorders (DCD) display deficits in planning, executing and controlling movements, concomitant with deficits in executive functions. Thus, are early sensorimotor atypicalities at the origin of long-lasting abnormal development of brain anatomy and functions? We hypothesize that degraded locomotor outcomes in adulthood originate as a consequence of early atypical sensorimotor experiences that induce developmental disorganization of sensorimotor circuitry. We showed recently that postnatal sensorimotor restriction (SMR), through hind limb immobilization from birth to one month, led to enduring digitigrade locomotion with ankle-knee overextension, degraded musculoskeletal tissues (e.g., gastrocnemius atrophy), and clear signs of spinal hyperreflexia in adult rats, suggestive of spasticity; each individual disorder likely interplaying in self-perpetuating cycles. In the present study, we investigated the impact of postnatal SMR on the anatomical and functional organization of hind limb representations in the sensorimotor cortex and processes representative of maladaptive neuroplasticity. We found that 28 days of daily SMR degraded the topographical organization of somatosensory hind limb maps, reduced both somatosensory and motor map areas devoted to the hind limb representation and altered neuronal response properties in the sensorimotor cortex several weeks after the cessation of SMR. We found no neuroanatomical histopathology in hind limb sensorimotor cortex, yet increased glutamatergic neurotransmission that matched clear signs of spasticity and hyperexcitability in the adult lumbar spinal network. Thus, even in the absence of a brain insult, movement disorders and brain dysfunction can emerge as a consequence of reduced and atypical patterns of motor outputs and somatosensory feedback that induce maladaptive neuroplasticity. Our results may contribute to understanding the inception and mechanisms underlying neurodevelopmental disorders, such as DCD.
Published: 2018

6. Analysis of CLCNKB mutations at dimer-interface, calcium binding site and pore reveals a variety of functional alterations in ClC-Kb channel leading to Bartter syndrome

Author: Marc Paulais, Imene Sakhi, Mathilde Keck, Yohan Bignon, Olga Andrini, Gabrielle Planelles, Naziha Bakouh, Sara Bitam, Nadia Frachon, Jacques Teulon, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Métabolisme et physiologie rénales (ERL 8228), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Espace et action, Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paulais, Marc, Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: kidney, chloride channel, Xenopus, [SDV]Life Sciences [q-bio], Mutant, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, medicine.disease_cause, Bartter syndrome, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, CLCNKB, Cell Line, 03 medical and health sciences, Chloride Channels, Genetics, medicine, Animals, Humans, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, Binding Sites, biology, Endoplasmic reticulum, 030305 genetics & heredity, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, biology.organism_classification, ClC-Kb, 3. Good health, Cell biology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Protein Transport, Chloride channel, biology.protein, Oocytes, Calcium, Protein Multimerization, mutation, Intracellular, Protein Binding
Abstract: International audience; Pathological missense mutations in CLCNKB gene give a wide spectrum of clinical phenotypes in Bartter syndrome type III patients. Molecular analysis of the mutated ClC-Kb channels can be helpful to classify the mutations according to their functional alteration. We investigated the functional consequences of nine mutations in the CLCNKB gene causing Bartter syndrome. We first established that all tested mutations lead to decreased ClC-Kb currents. Combining electrophysiological and biochemical methods in Xenopus laevis oocytes and in MDCKII cells, we identified three classes of mutations. One class is characterized by altered channel trafficking. p.A210V, p.P216L, p.G424R, and p.G437R are totally or partially retained in the endoplasmic reticulum. p.S218N is characterized by reduced channel insertion at the plasma membrane and altered pH-sensitivity; thus, it falls in the second class of mutations. Finally, we found a novel class of functionally inactivated mutants normally present at the plasma membrane. Indeed, we found that p.A204T alters the pH-sensitivity, p.A254V abolishes the calcium-sensitivity. p.G219C and p.G465R are probably partially inactive at the plasma membrane. In conclusion, most pathogenic mutants accumulate partly or totally in intracellular compartments, but some mutants are normally present at the membrane surface and simultaneously show a large range of altered channel gating properties.
Published: 2019

7. From cerebral palsy to developmental coordination disorder: Development of preclinical rat models corresponding to recent epidemiological changes

Author: Marine Kochmann, Maxime Delcour, Masahiro Tsuji, Ana Elisa Toscano, Mary F. Barbe, Jacques-Olivier Coq, Florence Cayetanot, Diego Cabral Lacerda, Marie-Hélène Canu, Hanane Khalki, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal de Pernambuco [Recife] (UFPE), Laboratoire Interdisciplinaire de Recherche en Sciences et Techniques, Faculté Polydisciplinaire de Béni-Mellal, Université Sultan Moulay Slimane (USMS ), Université de Montréal (UdeM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), National cerebral and cardiovascular center research institute, Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Kyoto Women's University, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Univ. Artois, Univ. Littoral Côte d’Opale, Institut de Neurosciences de la Timone [INT], Neurosciences sensorielles et cognitives [NSC], Federal University of Pernambuco [Recife], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369, and Kyoto University
Subjects: 030506 rehabilitation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain damage, Hyperreflexia, Developmental Coordination Disorder, Somatosensory system, Cerebral palsy, 03 medical and health sciences, 0302 clinical medicine, Cortex (anatomy), Neuroplasticity, Medicine, Animals, Humans, Orthopedics and Sports Medicine, Spasticity, Gait, White matter injury, business.industry, Rehabilitation, medicine.disease, Intrauterine growth retardation, Rats, Motor Skills Disorders, Hypoperfusion, medicine.anatomical_structure, Sensorimotor restriction, Sensorimotor Cortex, Prematurity, medicine.symptom, 0305 other medical science, business, Neuroscience, 030217 neurology & neurosurgery, Locomotion, Motor cortex
Abstract: International audience; Cerebral palsy (CP) is a complex syndrome of various sensory, motor and cognitive deficits. Its prevalence has recently decreased in some developed countries and its symptoms have also shifted since the 1960s. From the 1990s, CP has been associated with prematurity, but recent epidemiologic studies show reduced or absent brain damage, which recapitulates developmental coordination disorder (DCD). In previous studies, we developed a rat model based on mild intrauterine hypoperfusion (MIUH) that recapitulated the diversity of symptoms observed in preterm survivors. Briefly, MIUH led to early inflammatory processes, diffuse brain damage, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory (S1) cortex but not in the motor cortex (M1), delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, and memory and learning impairments in adult rats. Adult MIUH rats also exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. We recently developed a rat model of DCD based on postnatal sensorimotor restriction (SMR) without brain damage. Briefly, SMR led to digitigrade locomotion (i.e., “toe walking”) related to ankle-knee overextension, degraded musculoskeletal tissues (e.g., gastrocnemius atrophy), and lumbar hyperreflexia. The postnatal SMR then led to secondary degradation of the hind-limb maps in S1 and M1 cortices, altered cortical response properties and cortical hyperexcitability, but no brain damage. Thus, our 2 rat models appear to recapitulate the diversity of symptoms ranging from CP to DCD and contribute to understanding the emergence and mechanisms underlying the corresponding neurodevelopmental disorders. These preclinical models seem promising for testing strategies of rehabilitation based on both physical and cognitive training to promote adaptive brain plasticity and to improve physical body conditions.
Published: 2019

8. NI956/QGC006, a Potent Orally Active, Brain-Penetrating Aminopeptidase A Inhibitor for Treating Hypertension

Author: Catherine Llorens-Cortes, Mathilde Keck, Adrien Flahault, Fabrice Balavoine, Nicolas Inguimbert, Bernard P. Roques, Hugo De Almeida, Delphine Compere, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Quantum Genomics, Centre de recherches insulaires et observatoire de l'environnement (CRIOBE), Université de Perpignan Via Domitia (UPVD)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence CORAIL (LabEX CORAIL), Université des Antilles (UA)-Institut d'écologie et environnement-Université de la Nouvelle-Calédonie (UNC)-Université de la Polynésie Française (UPF)-Université de La Réunion (UR)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Université des Antilles et de la Guyane (UAG)-Institut de Recherche pour le Développement (IRD), UFR des Sciences Pharmaceutiques et Biologiques, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Perpignan Via Domitia (UPVD)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), USR 3278, PSL EPHE-CNRS-UPVD, USR 3278, CRIOBE, Labex Corail, University of Perpignan, France, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)
Subjects: Male, [SDV]Life Sciences [q-bio], Angiotensin III, Blood Pressure, 030204 cardiovascular system & hematology, Pharmacology, Glutamyl Aminopeptidase, Rats, Inbred WKY, Natriuresis, Renin-Angiotensin System, 03 medical and health sciences, 0302 clinical medicine, Aminopeptidase A, Rats, Inbred SHR, Renin–angiotensin system, Internal Medicine, Animals, Medicine, Disulfides, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, business.industry, Brain, Prodrug, Rats, 3. Good health, Disease Models, Animal, Blood pressure, Orally active, Hypertension, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sulfonic Acids, business
Abstract: Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We have shown that aminopeptidase A is involved in the formation of brain angiotensin III, which exerts tonic stimulatory control over blood pressure in hypertensive deoxycorticosterone acetate-salt rats and spontaneously hypertensive rats. We have also shown that injection of the specific and selective aminopeptidase A inhibitor, (3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid (EC33), by central route or its prodrug, RB150/firibastat, by oral route inhibited brain aminopeptidase A activity and blocked the formation of brain angiotensin III, normalizing blood pressure in hypertensive rats. These findings identified brain aminopeptidase A as a potential new therapeutic target for hypertension. We report here the development of a new aminopeptidase A inhibitor prodrug, NI956/QGC006, obtained by the disulfide bridge-mediated dimerization of NI929. NI929 is 10× more efficient than EC33 at inhibiting recombinant mouse aminopeptidase A activity in vitro. After oral administration at a dose of 4 mg/kg in conscious deoxycorticosterone acetate-salt rats, NI956/QGC006 normalized brain aminopeptidase A activity and induced a marked decrease in blood pressure of −44±13 mm Hg 4 hours after treatment ( P< 0.001), sustained over 10 hours (−21±12 mm Hg; P< 0.05). Moreover, NI956/QGC006 decreased plasma arginine-vasopressin levels, and increased diuresis and natriuresis, that may participate to the blood pressure decrease. Finally, NI956/QGC006 did not affect plasma sodium and potassium concentrations. This study shows that NI956/QGC006 is a best-in-class central-acting aminopeptidase A inhibitor prodrug. Our results support the development of hypertension treatments targeting brain aminopeptidase A.
Published: 2019

9. Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents

Author: Gavin Y. Oudit, Tess Lamer, Wang Wang, Xavier Iturrioz, John C. Vederas, Shaun M. K. McKinnie, Catherine Llorens-Cortes, Conrad Fischer, Institute of Organic Chemistry [Freiberg], Technishe Universität Bergakademie Freiberg (TU Bergakademie Freiberg), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife
Subjects: Arginine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Blood Pressure, 01 natural sciences, Polyethylene Glycols, 03 medical and health sciences, Palmitoylation, Drug Discovery, medicine, Humans, [CHIM]Chemical Sciences, Neprilysin, Plasma Kallikrein, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Apelin receptor, Pharmacology, 0303 health sciences, Protease, 010405 organic chemistry, Chemistry, Protein Stability, Organic Chemistry, Fatty Acids, General Medicine, Kallikrein, 0104 chemical sciences, Apelin, Biochemistry, Proteolysis, PEGylation
Abstract: Apelins are human peptide hormones with various physiological activities, including the moderation of cardiovascular, renal, metabolic and neurological function. Their potency is dependent on and limited by proteolytic degradation in the circulatory system. Here we identify human plasma kallikrein (KLKB1) as a protease that cleaves the first three N-terminal amino acids (KFR) of apelin-17. The cleavage kinetics are similar to neprilysin (NEP), which cleaves within the critical 'RPRL'-motif thereby inactivating apelin. The resulting C-terminal 14-mer after KLKB1 cleavage has much lower biological activity, and the presence of its N-terminal basic arginine seems to negate the blood pressure lowering effect. Based on C-terminally engineered apelin analogs (A2), resistant to angiotensin converting enzyme 2 (ACE2), attachment of an N-terminal C16 fatty acid chain (PALMitoylation) or polyethylene glycol chain (PEGylation) minimizes KLKB1 cleavage of the 17-mers, thereby extending plasma half-life while fully retaining biological activity. The N-terminally PEGylated apelin-17(A2) is a highly protease resistant analog, with excellent apelin receptor activation and pronounced blood pressure lowering effect.
Published: 2019

10. Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice

Author: Fabrice Balavoine, Onnik Agbulut, Solène Emmanuelle Boitard, Catherine Llorens-Cortes, Nathalie Mougenot, Mathilde Keck, Yannick Marc, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Quantum Genomics, Coeur, Muscle et Vaisseaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Cardiac function curve, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Angiotensin III, Myocardial Infarction, Administration, Oral, Cardiomegaly, 030204 cardiovascular system & hematology, Glutamyl Aminopeptidase, Renin-Angiotensin System, Mice, 03 medical and health sciences, 0302 clinical medicine, Enalapril, Fibrosis, Internal medicine, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Myocardial infarction, Enzyme Inhibitors, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Heart Failure, Ejection fraction, business.industry, Brain, Heart, Stroke Volume, medicine.disease, [SDV] Life Sciences [q-bio], CTGF, Disease Models, Animal, 030104 developmental biology, Endocrinology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Heart failure, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Inflammation Mediators, Cardiology and Cardiovascular Medicine, business, Biomarkers, medicine.drug
Abstract: Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. We hypothesized that orally administered firibastat (previously named RB150), an APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Two days after MI, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI + vehicle), firibastat (150 mg/kg; MI + firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI + enalapril) as a positive control. From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment normalized brain APA hyperactivity, with a return to the control values measured in sham group two weeks after MI. Four and six weeks after MI, MI + firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI + vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MI + firibastat mice displayed lower levels of mRNA for Ctgf and collagen types I and III (markers of fibrosis) than MI + vehicle mice. Thus, chronic oral firibastat administration after MI in mice prevents cardiac dysfunction by normalizing brain APA hyperactivity, and attenuates cardiac hypertrophy and fibrosis.
Published: 2019

11. Directed Molecular Evolution of an Engineered Gammaretroviral Envelope Protein with Dual Receptor Use Shows Stable Maintenance of Both Receptor Specificities

Author: Shervin Bahrami, Jonas Thomsen, Rodrigo Alvear-Perez, Finn Skou Pedersen, Xavier Iturrioz, Catherine Llorens-Cortes, Kristina Pagh Friis, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], viruses, Immunology, B-cell receptor, Microbiology, Genomic Instability, Cell Line, Receptors, G-Protein-Coupled, Viral vector, 03 medical and health sciences, Viral Envelope Proteins, Viral envelope, Viral entry, Virology, Murine leukemia virus, Animals, Humans, [CHIM]Chemical Sciences, Receptor, ComputingMilieux_MISCELLANEOUS, Apelin receptor, Gammaretrovirus, Apelin Receptors, biology, Virus Internalization, biology.organism_classification, Molecular biology, Virus-Cell Interactions, Viral Tropism, 030104 developmental biology, Insect Science, Receptors, Virus, Directed Molecular Evolution, Xenotropic and Polytropic Retrovirus Receptor
Abstract: We have previously reported the construction of a murine leukemia virus-based replication-competent gammaretrovirus (SL3-AP) capable of utilizing the human G protein-coupled receptor APJ (hAPJ) as its entry receptor and its natural receptor, the murine Xpr1 receptor, with equal affinities. The apelin receptor has previously been shown to function as a coreceptor for HIV-1, and thus, adaptation of the viral vector to this receptor is of significant interest. Here, we report the molecular evolution of the SL3-AP envelope protein when the virus is cultured in cells harboring either the Xpr1 or the hAPJ receptor. Interestingly, the dual receptor affinity is maintained even after 10 passages in these cells. At the same time, the chimeric viral envelope protein evolves in a distinct pattern in the apelin cassette when passaged on D17 cells expressing hAPJ in three separate molecular evolution studies. This pattern reflects selection for reduced ligand-receptor interaction and is compatible with a model in which SL3-AP has evolved not to activate hAPJ receptor internalization. IMPORTANCE Few successful examples of engineered retargeting of a retroviral vector exist. The engineered SL3-AP envelope is capable of utilizing either the murine Xpr1 or the human APJ receptor for entry. In addition, SL3-AP is the first example of an engineered retrovirus retaining its dual tropism after several rounds of passaging on cells expressing only one of its receptors. We demonstrate that the virus evolves toward reduced ligand-receptor affinity, which sheds new light on virus adaptation. We provide indirect evidence that such reduced affinity leads to reduced receptor internalization and propose a novel model in which too rapid receptor internalization may decrease virus entry.
Published: 2016

12. Dual enkephalinase inhibitor PL265: a novel topical treatment to alleviate corneal pain and inflammation

Author: Cyrine Ben-Dhaou, Hervé Poras, Christophe Baudouin, Stéphane Melik Parsadaniantz, Wurm Michel, Annabelle Réaux-Le Goazigo, Tanja Ouimet, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de la Vision, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Lipopolysaccharides, Male, genetic structures, [SDV]Life Sciences [q-bio], Administration, Topical, Narcotic Antagonists, Pharmacology, Corneal inflammation, Cornea, Mice, 0302 clinical medicine, Medicine, Enkephalinase inhibitor, Enzyme Inhibitors, ComputingMilieux_MISCELLANEOUS, Endogenous opioid, Naloxone, 3. Good health, Nociception, Neurology, Trigeminal Ganglion, Hyperalgesia, medicine.symptom, Benzalkonium Compounds, medicine.drug, Pain Threshold, Analgesic, Pain, Inflammation, 03 medical and health sciences, Animals, Opioid peptide, business.industry, eye diseases, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Anesthesiology and Pain Medicine, Opioid, Sensory System Agents, Anti-Infective Agents, Local, sense organs, Neurology (clinical), Capsaicin, Propionates, business, 030217 neurology & neurosurgery, Corneal Injuries
Abstract: Ocular pain is a core symptom of inflammatory or traumatic disorders affecting the anterior segment. To date, the management of chronic ocular pain remains a therapeutic challenge in ophthalmology. The main endogenous opioids (enkephalins) play a key role in pain control but exhibit only transient analgesic effects due to their rapid degradation. The aim of this study was to explore the antinociceptive and anti-inflammatory effects of topical administration of PL265 (a dual enkephalinase inhibitor) on murine models of corneal pain. On healthy corneas, chronic PL265 topical administration did not alter corneal integrity nor modify corneal mechanical and chemical sensitivity. Then, on murine models of corneal pain, we showed that repeated instillations of PL265 (10 mM) significantly reduced corneal mechanical and chemical hypersensitivity. PL265-induced corneal analgesia was completely antagonized by naloxone methiodide, demonstrating that PL265 antinociceptive effects were mediated by peripheral corneal opioid receptors. Moreover, flow cytometry (quantification of CD11b+ cells) and in vivo confocal microscopy analysis revealed that instillations of PL265 significantly decreased corneal inflammation in a corneal inflammatory pain model. Chronic PL265 topical administration also decreased Iba1 and neuronal injury marker (ATF3) staining in the nucleus of primary sensory neurons of ipsilateral trigeminal ganglion. These results open a new avenue for ocular pain treatment based on the enhancement of endogenous opioid peptides' analgesic effects in tissues of the anterior segment of the eye. Dual enkephalinase inhibitor PL265 seems to be a promising topical treatment for safe and effective alleviation of ocular pain and inflammation.
Published: 2018

13. Mild Intrauterine Hypoperfusion Leads to Lumber and Cortical Hyperexcitability, Spasticity, and Muscle Dysfunctions in Rats:Implications for Prematurity

Author: Coq, Jacques-Olivier, Delcour, Maxime, Ogawa, Yuko, Peyronnet, Julie, Castets, Francis, Turle-Lorenzo, Nathalie, Montel, Valérie, Bodineau, Laurence, Cardot, Phillipe, Brocard, Cécile, Liabeuf, Sylvie, Bastide, Bruno, Canu, Marie-Hélène, Tsuji, Masahiro, Cayetanot, Florence, Univ. Littoral Côte d’Opale, Univ. Artois, Université de Lille, Institut de Neurosciences de la Timone [INT], Aix Marseille Université [AMU], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS], Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Montréal (UdeM), National cerebral and cardiovascular center research institute, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université d'Artois (UA)-Université de Lille-Université du Littoral Côte d'Opale (ULCO), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Coq, Jacques-Olivier
Subjects: cerebral palsy, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neurology, white matter injury, intrauterine growth retardation, KCC2, neonatal hypoxia-ischemia, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Original Research
Abstract: International audience; Intrauterine ischemia-hypoxia is detrimental to the developing brain and leads to white matter injury (WMI), encephalopathy of prematurity (EP), and often to cerebral palsy (CP), but the related pathophysiological mechanisms remain unclear. In prior studies, we used mild intrauterine hypoperfusion (MIUH) in rats to successfully reproduce the diversity of clinical signs of EP, and some CP symptoms. Briefly, MIUH led to inflammatory processes, diffuse gray and WMI, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory and motor cortices, delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, memory and learning impairments. In the present study, we investigated the early and long-lasting mechanisms of pathophysiology that may be responsible for the various symptoms induced by MIUH. We found early hyperreflexia, spasticity and reduced expression of KCC2 (a chloride cotransporter that regulates chloride homeostasis and cell excitability). Adult MIUH rats exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. Taken together, these results show that reduced expression of KCC2, lumbar hyperreflexia, spasticity, altered properties of the soleus muscle, as well as cortical hyperexcitability may likely interplay into a self-perpetuating cycle, leading to the emergence, and persistence of neurodevelopmental disorders (NDD) in EP and CP, such as sensorimotor impairments, and probably hyperactivity, attention, and learning disorders.
Published: 2018

14. Involvement of arginine 878 together with Ca2+ in mouse aminopeptidase A substrate specificity for N-terminal acidic amino-acid residues

Author: Couvineau, Pierre, de Almeida, Hugo, Maigret, Bernard, Llorens-Cortes, Catherine, Iturrioz, Xavier, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Maigret, Bernard, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CNRS, INSERM, Collège de France, ANR RPIB and LabCom, Laboratory of central neuropeptides in the regulation of body fluid homeostasis and cardiovascular functions, INSERM U1050, Paris, F-75005, France, 2 Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, F-75005, France, Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI), Knowledge representation, reasonning (ORPAILLEUR), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL)
Subjects: Mutagenesis and Gene Deletion Techniques, [SDV]Life Sciences [q-bio], Fluorescent Antibody Technique, lcsh:Medicine, Molecular Dynamics, Biochemistry, Substrate Specificity, Mice, Computational Chemistry, Catalytic Domain, [CHIM] Chemical Sciences, Amino Acids, Cloning, Molecular, lcsh:Science, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Crystallography, Alanine, Organic Compounds, Hydrolysis, Physics, Acidic Amino Acids, Chemical Reactions, Condensed Matter Physics, Molecular Docking Simulation, Site-Directed Mutagenesis, [SDV] Life Sciences [q-bio], Chemistry, Physical Sciences, Crystal Structure, Cell lines, Basic Amino Acids, MESH: aminopeptidase A, molecular dynamics, molecular docking, site directed mutagenesis, Biological cultures, psychological phenomena and processes, Research Article, education, CHO Cells, Molecular Dynamics Simulation, Arginine, Glutamyl Aminopeptidase, Research and Analysis Methods, Cricetulus, mental disorders, Animals, Humans, Solid State Physics, [CHIM]Chemical Sciences, Molecular Biology Techniques, Molecular Biology, Lysine, Organic Chemistry, lcsh:R, Chemical Compounds, Biology and Life Sciences, Proteins, Aliphatic Amino Acids, Mutagenesis, Site-Directed, Calcium, lcsh:Q, Sulfonic Acids, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; Aminopeptidase A (APA) is a membraneboundzinc metalloprotease cleaving in thebrain the N-terminal aspartyl residue ofangiotensin II to generate angiotensin III,which exerts a tonic stimulatory effect on thecontrol of blood pressure in hypertensiveanimals. We built by homology a threedimensional(3D) model of human APA withCa2+ using the crystal structure of human APAas a template and we subsequently docked theAPA inhibitor EC33 [(3S)-3-amino-4-sulfanylbutane-1-sulfonicacid]. We report the presencein the S1 subsite of Arg-887 (Arg-878 in mouseAPA), the guanidium moiety of whichestablished an interaction with theelectronegative sulfonate group of EC33.Mutagenic replacement of Arg-878 with analanine or lysine residue led to a decrease in theaffinity of the recombinant enzymes for theacidic substrate, α-L-glutamyl-β-naphthylamide, with a slight decrease insubstrate hydrolysis velocity either in theabsence or presence of Ca2+. In the absence ofCa2+, the mutations modified the substratespecificity of APA for the acidic substrate, themutated enzymes hydrolyzing more efficientlybasic and neutral substrates, nevertheless theaddition of Ca2+ partially restored their acidicsubstrate specificity. An analysis of the 3Dmodels of the Arg-878 mutants revealed achange in the volume of the S1 subsite, whichmay impair the binding and/or the optimalpositioning of the substrate in the active site aswell as its hydrolysis. These findingsdemonstrate a key role of Arg-878 in APAsubstrate specificity for N-terminal acidicamino acids by insuring the optimal positioningof the substrate during catalysis.
Published: 2017

15. Synthetic Modification within the 'RPRL' Region of Apelin Peptides: Impact on Cardiovascular Activity and Stability to Neprilysin and Plasma Degradation

Author: Kevin R. Kalin, John C. Vederas, Xavier Iturrioz, Gavin Y. Oudit, Wang Wang, Conrad Fischer, Shaun M. K. McKinnie, Catherine Llorens-Cortes, Tyler McDonald, Institute of Organic Chemistry [Freiberg], Technishe Universität Bergakademie Freiberg (TU Bergakademie Freiberg), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife
Subjects: 0301 basic medicine, Agonist, Proteases, medicine.drug_class, Proteolysis, [SDV]Life Sciences [q-bio], Blood Pressure, CHO Cells, Peptide hormone, Receptors, G-Protein-Coupled, Mice, Structure-Activity Relationship, 03 medical and health sciences, Cricetulus, 0302 clinical medicine, Heart Rate, Drug Discovery, medicine, Animals, Humans, Protein Isoforms, [CHIM]Chemical Sciences, Receptor, Neprilysin, ComputingMilieux_MISCELLANEOUS, Apelin receptor, Apelin Receptors, medicine.diagnostic_test, Chemistry, fungi, Cardiovascular Agents, Stereoisomerism, Rats, Apelin, 030104 developmental biology, Biochemistry, Intercellular Signaling Peptides and Proteins, Molecular Medicine, 030217 neurology & neurosurgery
Abstract: Apelin is an important mammalian peptide hormone with a range of physiological roles, especially in the cardiovascular system. The apelinergic system is a promising target for treatment of disease, but this remains to be realized due to rapid proteolysis of apelin-derived peptides by proteases, including neprilysin (NEP). The synthetic analogues modified within the NEP degradation site ("RPRL" motif) showed improved in vitro proteolytic stability while maintaining receptor-binding affinities, with three candidate peptides retaining full cardiovascular activities for potential therapeutic application. Many such analogues proved physiologically inactive even with relatively conservative modifications, highlighting the importance of this region for full agonist activity of this peptide hormone.
Published: 2017

16. Design and validation of the first cell-impermeant melatonin receptor agonist

Author: Gbahou, Florence, Cecon, Erika, Viault, Guillaume, Gerbier, Romain, Jean-Alphonse, Frédéric, Karamitri, Angeliki, Guillaumet, Gérald, Delagrange, Philippe, Friedlander, Robert, Vilardaga, Jean-Pierre, Suzenet, Franck, Jockers, Ralf, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Unité de Recherches et Découvertes en Neurosciences, Institut de Recherches Servier, University of Pittsburgh (PITT), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), INSERM U691 - Collège de France, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC)
Subjects: [SDV]Life Sciences [q-bio], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction
Abstract: International audience; BACKGROUND AND PURPOSEThe paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT1 and MT2 receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools.EXPERIMENTAL APPROACHWe therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy.KEY RESULTSAmong the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MT1 and MT2 receptors. ICOA-13 showed differential activities on melatonin receptors ranging from partial to full agonistic properties for the Gi/cAMP and ERK pathway and beta-arrestin 2 recruitment. Notably, ICOA-13 enabled us to discriminate between Gi/cAMP signalling of the MT1 receptor initiated at the cell surface and neuronal mitochondria.CONCLUSIONS AND IMPLICATIONSWe report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT1 receptors may have an important impact on the development of novel melatonin receptor ligands relevant for neurodegenerative diseases, such as Huntington disease.
Published: 2017

17. Structure-function studies by molecular modeling and site-directed mutagenesis of potential therapeutic targets involved in the regulation of body fluid homeostasis and cardiovascular functions

Author: Couvineau, Pierre, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité, Catherine Llorens-Cortes, and Xavier Iturrioz
Subjects: Structure-Activity-Relationship studies, Molecular biology, Biochimie, Enzymologie, Site-Directed mutagenesis, Cardiovascular functions, Molecular modeling, Heart failure, G-Coupled Protein Receptor, Pharmacologie, Biochemistry, Biologie Cellulaire, Structure-Function studies, Mutagénèse dirigée, Body fluid homeostasis, Cellular biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Aminopeptidase A, Etudes structure-Fonction, Pharmacology, Equilibre hydrique, Zinc metallopeptidase, Récepteur Couplé aux Protéines G, Biologie moléculaire, Etudes structure-Activité, Fonctions cardiovasculaires, Apéline, Insuffisance cardiaque, Métallopeptidase monozinc, Hypertension, Enzymology, Apelin, Hyponatrémie, Modélisation moléculaire, Hyponatremia
Abstract: The doctoral work was divided in two parts, one on the structure-function studies of aminopeptidase A, and the second one, on those of the apelin receptor. I/Aminopeptidase A (APA) is a membrane bound monozinc aminopeptidase which generates, in the brain, angiotensin (Ang) III from Ang II. Ang III is one of the main effector peptides of the brain renin-angiotensin system, which exerts a tonic stimulatory action on the control of blood pressure in hypertensive rats. Thus, the blockade of brain APA by a specific and selective inhibitor, EC33 or its prodrug, RB150, normalizes blood pressure in two animal models of arterial hypertension (HTA). APA constitutes a potential therapeutic target for the treatment of HTA that justifies the development of more potent and selective APA inhibitors than EC33, with enhanced pharmacodynamic and pharmacokinetic profiles when compared to RB150. With this aim, we built a three dimensional (3D) model of APA based on the recently published crystal structure of human APA. We validated this model by structure-function studies combining molecular modeling and site-directed mutagenesis demonstrating the crucial role of one residue in the S1 subsite responsible for substrate specificity of APA for N-terminal acidic amino-acid residues and two other residues constituting the S2' subsite of APA involved in the binding of the P2' acidic residue of tripeptidic inhibitors, previously developed in the laboratory. II/Apelin is the endogenous ligand of the human orphan receptor named APJ (ApelinR), a G protein-coupled receptor. Apelin and ApelinR are involved in the control of body fluid homeostasis and cardiovascular functions. ApelinR constitutes a potential therapeutic target for the treatment of heart failure and water retentions. Given that apelin half-life in the blood circulation is in the minute range, we aimed to develop potent metabolically stable apelin analogs.. In this context, it is necessary to understand how apelin binds to ApelinR and how it is activated. To do so, we build a 3D model of ApelinR based on the crystal structure of the chemokine receptor, CXCR4. We validated this model by structure-function studies by molecular modeling and site-directed mutagenesis. We showed that apelin interacts with the receptor through interactions between the basic residues of the peptide and the acidic residues of the ApelinR, located in the extracellular loops. ,We then developed metabolically stable apelin-17 (K17F) analogs following two different strategies. First, we substituted each residue of K17F by its D-isomer or a synthetic amino-acid. Secondly, we added a fluoroalkyl chain at the N-terminal part of K17F. These two strategies allowed to significantly improve plasma half-life of the modified peptides for several hours without modifying their pharmacological properties as compared to K17F. Two apelin metabolically stable analogs, P92 and LIT01-196, were found to have significantly higher in vivo activity than K17F with a strong capacity to decrease blood pressure and to inhibit vasopressin release in the blood stream inducing an increased aqueous diuresis. These new validated 3D models will be now used to perform in silico screening of virtual chemical libraries to discover new APA inhibitors and ApelinR agonists that could ultimately lead to new drug candidates. These compounds could be useful for the treatment of HTA and heart failure.; Ces travaux de thèse s'articulent autour de deux projets : les études structure-fonction de l'aminopeptidase A, d'une part, et celles du récepteur de l'apéline, d'autre part. I/L'aminopeptidase A (APA, EC 3.4.11.7) est une aminopeptidase monozinc membranaire qui, dans le cerveau, produit l'angiotensine (Ang) III à partir de l'Ang II. L'Ang III est l'un des principaux peptides effecteurs du système rénine-angiotensine cérébral qui exerce un effet stimulateur tonique sur le contrôle central de la pression artérielle chez le rat hypertendu. Ainsi le blocage de l'APA par un inhibiteur spécifique et sélectif, l'EC33 ou sa prodrogue, le RB150, normalise la pression artérielle dans deux modèles expérimentaux d'hypertension artérielle (HTA). L'APA constitue une cible thérapeutique potentielle pour le traitement de l'HTA qui justifie le développement de nouveaux inhibiteurs de cette enzyme plus puissants et plus sélectifs que l'EC33 et avec un profil pharmacodynamique et pharmacocinétique amélioré par rapport au RB150. Pour cela, nous avons construit un modèle tridimensionnel (3D) de l'APA sur la base de la structure cristallographique de l'APA humaine récemment publiée. Nous avons ensuite validé ce modèle par des études structure-fonction par modélisation moléculaire et mutagénèse dirigée en démontrant l'implication, d'un résidu du sous-site S1 dans la spécificité de substrat acide de l'APA et de deux résidus formant le sous-site S2' interagissant avec le résidu P2' acide d'inhibiteurs tripeptidiques précédemment développés dans le laboratoire.II/L'apéline est le ligand naturel du récepteur orphelin humain APJ (ApélineR), un récepteur à sept domaines transmembranaires couplé aux protéines G. L'apéline et son récepteur sont impliqués dans le maintien de l'équilibre hydrique et des fonctions cardiovasculaires. L'ApélineR constitue une cible thérapeutique potentielle dans le traitement de l'insuffisance cardiaque et des rétentions hydriques. Etant donné que la demi-vie de l'apéline dans la circulation sanguine est de l'ordre de la minute, l'objectif est de développer des analogues de l'apéline métaboliquement stables. Pour développer de tels composés, nous avons entrepris de comprendre comment l'apéline se lie à son récepteur et comment elle l'active. Dans ce but, nous avons construit un modèle 3D de l'ApélineR basé sur la structure cristallographique du récepteur aux chimiokines, CXCR4. Nous avons validé ce modèle par des études structure-fonction par modélisation moléculaire et mutagénèse dirigée. Nous avons identifié à la surface du récepteur, les résidus acides des boucles extracellulaires qui interagissent avec les résidus basiques de l'apéline. Nous avons ensuite développé des analogues de l'apéline-17 (K17F) métaboliquement stables par deux stratégies différentes. Premièrement, nous avons substitué chacun des résidus de l'apéline par son énantiomère de la série D ou par un acide aminé synthétique. Deuxièmement, nous avons ajouté une chaîne fluoroalkyle à l'extrémité N-terminale de l'apéline. Ces deux stratégies ont permis d'obtenir plusieurs composés dont les plus actifs sont le P92 et le LIT01-196 qui conservent des propriétés pharmacologiques identiques à celles de K17F et qui présentent une demi-vie plasmatique largement supérieure à celle du peptide endogène. Ces deux analogues se sont révélés particulièrement actifs in vivo avec une capacité à diminuer la pression artérielle et à réduire la sécrétion de vasopressine dans le sang conduisant à une augmentation de la diurèse aqueuse. Les modèles 3D validés de l'APA et de l'ApélineR seront utilisés pour des campagnes de criblage in silico de chimiothèques virtuelles afin de découvrir de nouveaux inhibiteurs de l'APA et des agonistes de l'ApélineR qui pourraient conduire à terme à de nouveaux candidats-médicaments. Ces composés pourraient être utiles pour le traitement de l'HTA et de l'insuffisance cardiaque.
Published: 2017

18. Development of original metabolically stable apelin-17 analogs with diuretic and cardiovascular effects

Author: Iturrioz, Xavier, Gerbier, Romain, Alvear-Perez, Rodrigo, Margathe, Jean-François, Flahault, Adrien, Couvineau, Pierre, Gao, Ji, De Mota, Nadia, Dabire, Hubert, Li, Bo, Ceraudo, Bo, Hus-Citharel, Bo, Esteoulle, Lucie, Bisoo, Bo, Hibert, Marcel, Berdeaux, Alain, Iturrioz, Bo, Bonnet, Bo, Llorens-Cortes, Bo, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Pharmacologie des Dysfonctionnements Endotheliaux et Myocardiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), INSERM U955, équipe 3, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS-PSL), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Vasopressin, [SDV]Life Sciences [q-bio], Diuresis, CHO Cells, 030204 cardiovascular system & hematology, Biochemistry, Receptors, G-Protein-Coupled, Rats, Sprague-Dawley, Contractility, Mice, Structure-Activity Relationship, 03 medical and health sciences, Cricetulus, 0302 clinical medicine, In vivo, Cricetinae, Internal medicine, Genetics, medicine, Animals, [CHIM]Chemical Sciences, Amino Acid Sequence, Rats, Wistar, Diuretics, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Apelin receptor, Apelin Receptors, Chemistry, Cardiovascular Agents, Angiotensin II, Rats, 3. Good health, Apelin, 030104 developmental biology, Endocrinology, Vasoconstriction, Cardiovascular agent, Female, Peptides, Biotechnology
Abstract: Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling cardiovascular functions and water balance. Because the in vivo apelin half-life is in the minute range, we aimed to identify metabolically stable apelin-17 (K17F) analogs. We generated P92 by classic chemical substitutions and LIT01-196 by original addition of a fluorocarbon chain to the N terminus of K17F. Both analogs were much more stable in plasma (half-life >24 h for LIT01-196) than K17F (4.6 min). Analogs displayed a subnanomolar affinity for the apelin receptor and behaved as full agonists with regard to cAMP production, ERK phosphorylation, and apelin receptor internalization. Ex vivo, these compounds induced vasorelaxation of rat aortas and glomerular arterioles, respectively, precontracted with norepinephrine and angiotensin II, and increased cardiac contractility. In vivo, after intracerebroventricular administration in water-deprived mice, P92 and LIT01-196 were 6 and 160 times, respectively, more efficient at inhibiting systemic vasopressin release than K17F. Administered intravenously (nmol/kg range) in normotensive rats, these analogs potently increased urine output and induced a profound and sustained decrease in arterial blood pressure. In summary, these new compounds, which favor diuresis and improve cardiac contractility while reducing vascular resistances, represent promising candidates for the treatment of heart failure and water retention/hyponatremic disorders.-Gerbier, R., Alvear-Perez, R., Margathe, J.-F., Flahault, A., Couvineau, P., Gao, J., De Mota, N., Dabire, H., Li, B., Ceraudo, E., Hus-Citharel, A., Esteoulle, L., Bisoo, C., Hibert, M., Berdeaux, A., Iturrioz, X., Bonnet, D., Llorens-Cortes, C. Development of original metabolically stable apelin-17 analogs with diuretic and cardiovascular effects.
Published: 2017

19. Role of the Vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders

Author: Adrien Flahault, Pierre Couvineau, Rodrigo Alvear-Perez, Xavier Iturrioz, Catherine Llorens-Cortes, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, and Iturrioz, Xavier
Subjects: lcsh:RC648-665, urogenital system, vasopressin, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], metabolically stable apelin analogs, Review, lcsh:Diseases of the endocrine glands. Clinical endocrinology, apelin receptor, [SDV] Life Sciences [q-bio], apelin water metabolism disorders, diuresis, Endocrinology, apelin, [CHIM] Chemical Sciences, [CHIM]Chemical Sciences, G protein-coupled receptor, osmolality, ComputingMilieux_MISCELLANEOUS, hormones, hormone substitutes, and hormone antagonists
Abstract: Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. In animal models, experimental data demonstrate that intracerebroventricular injection of apelin into lactating rats inhibits the phasic electrical activity of arginine vasopressin (AVP) neurons, reduces plasma AVP levels, and increases aqueous diuresis. In the kidney, apelin increases diuresis by increasing the renal microcirculation and by counteracting the antidiuretic effect of AVP at the tubular level. Moreover, after water deprivation or salt loading, in humans and in rodents, AVP and apelin are conversely regulated to facilitate systemic AVP release and to avoid additional water loss from the kidney. Furthermore, apelin and vasopressin secretion are significantly altered in various water metabolism disorders including hyponatremia and polyuria-polydipsia syndrome. Since the in vivo half-life of apelin is in the minute range, metabolically stable apelin analogs were developed. The efficacy of these lead compounds for decreasing AVP release and increasing both renal blood flow and diuresis, make them promising candidates for the treatment of water retention and/or hyponatremic disorders.
Published: 2017

20. A new strategy for treating hypertension by blocking the activity of the brain renin–angiotensin system with aminopeptidase A inhibitors

Author: Catherine Llorens-Cortes, Yannick Marc, Vincent Leroux, Fabrice Balavoine, Ji Gao, Xavier Iturrioz, Pharmacologie des Dysfonctionnements Endotheliaux et Myocardiques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Quantum Genomics, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, medicine.medical_specialty, Vasopressin, [SDV]Life Sciences [q-bio], Angiotensin III, Blood Pressure, 030204 cardiovascular system & hematology, Glutamyl Aminopeptidase, Supraoptic nucleus, 03 medical and health sciences, 0302 clinical medicine, Spontaneously hypertensive rat, Internal medicine, Renin–angiotensin system, Animals, Humans, [CHIM]Chemical Sciences, Medicine, Protease Inhibitors, Disulfides, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Binding Sites, Clinical Trials, Phase I as Topic, business.industry, Brain, General Medicine, Rostral ventrolateral medulla, Angiotensin II, Subfornical organ, Rats, 3. Good health, medicine.anatomical_structure, Endocrinology, Blood-Brain Barrier, Drug Design, Hypertension, Mutagenesis, Site-Directed, Sulfonic Acids, business
Abstract: Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin–angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood–brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial. Abbreviations: ACE, angiotensin-converting enzyme; ACEI, angiotensin-converting enzyme inhibitor; AGT, angiotensinogen; AngI etc., angiotensin I etc; Ang-(1–7), angiotensin-(1–7); APA, aminopeptidase A; APN, aminopeptidase N; AT1R, AngII type 1 receptor; AT2R, AngII type 2 receptor; AVP, arginine-vasopressin; BBB, blood–brain barrier; BP, blood pressure; DOCA, deoxycorticosterone acetate; GluPO3H2, 4-amino-4 phosphonobutyric acid; GluSH, glutamate thiol; HR, heart rate; i.c.v., intracerebroventricular(ly); LTA4H, leukotriene A4 hydrolase; MABP, mean arterial BP; NEP, neutral endopeptidase 24.11; NOAEL, no observed adverse effect level; NTS, nucleus of the tractus solitaries; OVLT, organum vasculosum of the lamina terminalis; p.o., per os; PVN, paraventricular nucleus; RAS, renin–angiotensin system; RVLM, rostroventrolateral medulla; SFO, subfornical organ; SHR, spontaneously hypertensive rat; SON, supraoptic nucleus; WKY, Wistar–Kyoto
Published: 2014

21. Central Apelin Controls Glucose Homeostasisviaa Nitric Oxide-Dependent Pathway in Mice

Author: Sophie Rastrelli, André Colom, Bernard Frances, Isabelle Castan-Laurell, Nathalie M. Delzenne, Isabelle Leclercq, Philippe Valet, Patrice D. Cani, Thibaut Duparc, Lionel Moulédous, Claude Knauf, Nicolas Massaly, J. Andrew Pospisilik, Catherine Llorens-Cortes, Sophie Le Gonidec, Anne Drougard, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Metabolism and nutrition research group, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Louvain Drug Research Institute (LDRI), Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratory of hepato-gastroenterology, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Institut de Recherche Experimentale et Clinique, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of immunobiology, Max-Planck-Institut, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Physiology, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Adipose tissue, Biochemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, Insulin Secretion, Hyperinsulinemia, Homeostasis, Insulin, Glucose homeostasis, General Environmental Science, Neurons, 0303 health sciences, Brain, Circadian Rhythm, 3. Good health, Apelin, [SDV] Life Sciences [q-bio], Infusions, Intraventricular, Intercellular Signaling Peptides and Proteins, medicine.medical_specialty, Hypothalamus, 030209 endocrinology & metabolism, Carbohydrate metabolism, Nitric Oxide, Diabetes Mellitus, Experimental, Nitric oxide, 03 medical and health sciences, Insulin resistance, Adipokines, Internal medicine, medicine, Animals, Humans, Molecular Biology, 030304 developmental biology, business.industry, Cell Biology, medicine.disease, Biosynthetic Pathways, Glucose, Endocrinology, Diabetes Mellitus, Type 2, chemistry, General Earth and Planetary Sciences, Insulin Resistance, business
Abstract: International audience; Abstract Aims: Apelin and its receptor have emerged as promising targets for the treatment of insulin resistance. Indeed, peripheral administration of apelin stimulates glucose utilization and insulin sensitivity via a nitric oxide (NO) pathway. In addition to being expressed on peripheral metabolically active adipose tissues, apelin is also found in the brain. However, no data are available on the role of central effects of apelin on metabolic control. We studied glucose metabolism in response to acute and chronic intracerebroventricular (i.c.v.) injection of apelin performed in normal and obese/diabetic mice. Results: We demonstrate that i.c.v. injection of apelin into fed mice improves glucose control via NO-dependent mechanisms. These results have been strengthened by transgenic (eNOS-KO mice), pharmacological (L-NMMA i.c.v. treated mice), and real-time measurement of NO release with amperometric probes detection. High-fat diet-fed mice displayed a severely blunted response to i.c.v. apelin associated with a lack of NO response by the hypothalamus. Moreover, central administration of high dose apelin in fasted normal mice provoked hyperinsulinemia, hyperglycemia, glucose intolerance, and insulin resistance. Conclusion: These data provide compelling evidence that central apelin participates in the regulation of glucose homeostasis and suggest a novel pathophysiological mechanism involved in the transition from normal to diabetic state. Antioxid. Redox Signal. 15, 1477-1496.
Published: 2011

22. Reciprocal Regulation of Plasma Apelin and Vasopressin by Osmotic Stimuli

Author: Xavier Iturrioz, Séverine Peyrard, Anne Blanchard, Nicolas Chartrel, Nadia De Mota, Hubert Vaudry, Catherine Llorens-Cortes, Pierre Corvol, Michel Azizi, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CIC AP-HP (hegp Ex-Broussais)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Iturrioz, Xavier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Llorens Cortes, Catherine
Subjects: Male, Vasopressin, MESH: Renin, [SDV]Life Sciences [q-bio], MESH: Saline Solution, Hypertonic, MESH: Arginine Vasopressin, MESH: Body Fluids, Electrolytes, MESH: Osmolar Concentration, 0302 clinical medicine, MESH: Electrolytes, Renin, [CHIM] Chemical Sciences, Blood plasma, MESH: Blood Proteins, Homeostasis, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Chemistry, Blood Proteins, General Medicine, Water-Electrolyte Balance, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Body Fluids, Apelin, [SDV] Life Sciences [q-bio], Hematocrit, MESH: Homeostasis, Nephrology, Intercellular Signaling Peptides and Proteins, MESH: Drinking, hormones, hormone substitutes, and hormone antagonists, Adult, medicine.medical_specialty, Adolescent, Drinking, MESH: Hematocrit, 03 medical and health sciences, Clinical Research, Osmotic Pressure, Internal medicine, Renin–angiotensin system, medicine, Humans, [CHIM]Chemical Sciences, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Saline Solution, Hypertonic, MESH: Adolescent, MESH: Humans, Osmolar Concentration, MESH: Adult, MESH: Osmotic Pressure, MESH: Male, Hypertonic saline, Arginine Vasopressin, Plasma osmolality, Endocrinology, nervous system, MESH: Water-Electrolyte Balance, Magnocellular cell, 030217 neurology & neurosurgery
Abstract: International audience; Apelin is a neuropeptide that co-localizes with vasopressin (AVP) in magnocellular neurons and is involved in body fluid homeostasis. Osmotic stimuli have opposite effects on the regulation of apelin and AVP secretion in animal models, but whether this is true in humans is unknown. This study investigated the relationship among osmolality, apelin, and AVP in 10 healthy men after infusion of hypertonic saline or loading with water to increase and decrease plasma osmolality, respectively. Increasing plasma osmolality was accompanied by a parallel, linear increase in plasma AVP concentration and by a decrease in plasma apelin concentration. In contrast, decreasing plasma osmolality by water loading reduced plasma AVP concentration and rapidly increased plasma apelin concentration. These findings suggest that regulation of apelin secretion contributes to the maintenance of body fluid homeostasis.
Published: 2008

23. New structural insights into the apelin receptor: identification of key residues for apelin binding

Author: Bernard Maigret, Pierre Couvineau, Catherine Llorens-Cortes, Xavier Iturrioz, Rodrigo Alvear-Perez, Vincent Leroux, Romain Gerbier, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL)
Subjects: Models, Molecular, Molecular model, Protein Conformation, Recombinant Fusion Proteins, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Biochemistry, Receptors, G-Protein-Coupled, Cyclic AMP, Genetics, Animals, Humans, [CHIM]Chemical Sciences, Amino Acid Sequence, Binding site, Site-directed mutagenesis, Receptor, Molecular Biology, Conserved Sequence, ComputingMilieux_MISCELLANEOUS, Apelin receptor, G protein-coupled receptor, Apelin Receptors, Binding Sites, Sequence Homology, Amino Acid, Chemistry, molecular modeling, homology models, Rats, Apelin, Amino Acid Substitution, Structural Homology, Protein, Docking (molecular), G protein–coupled receptor, Multiprotein Complexes, APJ, Mutagenesis, Site-Directed, Intercellular Signaling Peptides and Proteins, site-directed mutagenesis, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Biotechnology
Abstract: International audience; Apelin is the endogenous ligand of the orphan 7-transmembrane domain GPCR APJ, now named the apelin receptor (ApelinR). Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To better understand the structural organization of the ApelinR, we built 3 homology 3-dimensional (3D) models of the human ApelinR using the validated cholecystokinin receptor-1 3D model or the X-ray structures of the β2-adrenergic and CXCR4 receptors as templates. Docking of the pyroglutamyl form of apelin 13 (pE13F) into these models revealed the conservation at the bottom of the binding site of a hydrophobic cavity in which the C-terminal Phe of pE13F was embedded. In contrast, at the top of the binding site, depending on the model, different interactions were visualized between acidic residues of the ApelinR and the basic residues of pE13F. Using site-directed mutagenesis, we showed that Asp 92, Glu 172, and Asp 282 of rat ApelinR are key residues in apelin binding by interacting with Lys 8, Arg 2, and Arg 4 of pE13F, respectively. These residues are only seen in the CXCR4-based ApelinR 3D model, further validating this model. These findings bring new insights into the structural organization of the ApelinR and the mode of apelin binding.
Published: 2015

24. Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists

Author: Denis Heissler, Dominique Bonnet, Rodrigo Alvear-Perez, Stéphanie Riché, Jean-François Margathe, Nassera Tounsi, Xavier Iturrioz, Catherine Llorens-Cortes, Maxime Kuhry, Hadjila Chabane, Claire Marsol, Marcel Hibert, Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche En Chimie Inorganique - EA 2067 (GRECI), Université de Reims Champagne-Ardenne (URCA), Synthèse, Biosynthèse et Activité de Biomolécules (SBAB), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB)
Subjects: Agonist, Spectrometry, Mass, Electrospray Ionization, medicine.drug_class, [SDV]Life Sciences [q-bio], Regulator, Context (language use), CHO Cells, Pharmacology, Ligands, Receptor, Angiotensin, Type 1, Receptors, G-Protein-Coupled, Mice, Plasma, Structure-Activity Relationship, Cricetulus, Drug Discovery, Cyclic AMP, medicine, Animals, [CHIM]Chemical Sciences, Receptor, ComputingMilieux_MISCELLANEOUS, Apelin receptor, Apelin Receptors, Molecular Structure, Drug discovery, Chemistry, Dipeptides, Fluoresceins, Ligand (biochemistry), Rats, 3. Good health, Apelin, Molecular Medicine
Abstract: Apelin is the endogenous ligand for the previously orphaned G protein-coupled receptor APJ. Apelin and its receptor are widely distributed in the brain, heart, and vasculature, and are emerging as an important regulator of body fluid homeostasis and cardiovascular functions. To further progress in the pharmacology and the physiological role of the apelin receptor, the development of small, bioavailable agonists and antagonists of the apelin receptor, is crucial. In this context, E339-3D6 (1) was described as the first nonpeptidic apelin receptor agonist. We show here that 1 is actually a mixture of polymethylated species, and we describe an alternative and versatile solid-phase approach that allows access to highly pure 27, the major component of 1. This approach was also applied to prepare a series of derivatives in order to identify the crucial structural determinants required for the ligand to maintain its affinity for the apelin receptor as well as its capacity to promote apelin receptor signaling and internalization. The study of the structure-activity relationships led to the identification of ligands 19, 21, and 38, which display an increased affinity compared to that of 27. The latter and 19 behave as full agonists with regard to cAMP production and apelin receptor internalization, whereas 21 is a biased agonist toward cAMP production. Interestingly, the three ligands display a much higher stability in mouse plasma (T1/210 h) than the endogenous apelin-17 peptide 2 (T1/24 min).
Published: 2014

25. Mechanisms Involved in Dual Vasopressin/Apelin Neuron Dysfunction during Aging

Author: Delpech, J.C., Sauvant, Julie, Delpech, Jean-Christophe, Palin, Karine, De Mota, Nadia, Dudit, Jennifer, Aubert, Agnès, Orcel, Hélène, Roux, Pascale, Layé, Sophie, Moos, Françoise, Llorens-Cortes, Catherine, Nadjar, Agnès, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Nutrition et Neurobiologie intégrée (NutriNeuro), Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Psychoneuroimmunologie, nutrition et génétique, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Équipe de recherches sur l'histoire, les théories et la didactique de la littérature et des arts du spectacle des 19e, 20e et 21e siècles (Traverses 19-21), Université Stendhal - Grenoble 3, Nutrition et Neurobiologie intégrée (NutriNeur0), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), HAL UPMC, Gestionnaire, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Vasopressin, Aging, microscopie, Anatomy and Physiology, [SDV]Life Sciences [q-bio], lcsh:Medicine, Minocycline, TRPV, neurone récepteur, Supraoptic nucleus, Transient receptor potential channel, 0302 clinical medicine, Aquaretic, Immune Physiology, cytokine, animal adulte, rat, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Neurons, 0303 health sciences, Multidisciplinary, Chemistry, Neurochemistry, vieillissement, peptide, Apelin, Anti-Bacterial Agents, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Intercellular Signaling Peptides and Proteins, Cytokines, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], hormones, hormone substitutes, and hormone antagonists, Research Article, medicine.medical_specialty, Vasopressins, TRPV Cation Channels, Neurophysiology, Endocrine System, animal jeune, 03 medical and health sciences, Osmotic Pressure, Internal medicine, medicine, Animals, Rats, Wistar, Biology, plasma, Neuroinflammation, 030304 developmental biology, Endocrine Physiology, Interleukin-6, lcsh:R, Neuroendocrinology, Rats, Endocrinology, Gene Expression Regulation, Astrocytes, vasopressine, lcsh:Q, Neuron, Physiological Processes, 030217 neurology & neurosurgery, Neuroscience
Abstract: International audience; Normal aging is associated with vasopressin neuron adaptation, but little is known about its effects on the release of apelin, an aquaretic peptide colocalized with vasopressin. We found that plasma vasopressin concentrations were higher and plasma apelin concentrations lower in aged rats than in younger adults. The response of AVP/apelin neurons to osmotic challenge was impaired in aged rats. The overactivity of vasopressin neurons was sustained partly by the increased expression of Transient receptor potential vanilloid2 (Trpv2), because central Trpv blocker injection reversed the age-induced increase in plasma vasopressin concentration without modifying plasma apelin concentration. The morphofunctional plasticity of the supraoptic nucleus neuron-astrocyte network normally observed during chronic dehydration in adults appeared to be impaired in aged rats as well. IL-6 overproduction by astrocytes and low-grade microglial neuroinflammation may contribute to the modification of neuronal functioning during aging. Indeed, central treatment with antibodies against IL-6 decreased plasma vasopressin levels and increased plasma apelin concentration toward the values observed in younger adults. Conversely, minocycline treatment (inhibiting microglial metabolism) did not affect plasma vasopressin concentration, but increased plasma apelin concentration toward control values for younger adults. This study is the first to demonstrate dual vasopressin/apelin adaptation mediated by inflammatory molecules and neuronal Trpv2, during aging.
Published: 2014

26. Brainstem and hypothalamic areas involved in respiratory chemoreflexes: a Fos study in adult rats

Author: Nicole Larnicol, Patrick Berquin, L. Bodineau, Françoise Gros, Dumonceaud, Corinne, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques, Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biotechnologies Végétales appliquées aux Plantes Aromatiques et Médicinales (LBVPAM), Université Jean Monnet [Saint-Étienne] (UJM), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques - EA UPJV 3901 (EA3901), Laboratoire de Biotechnologies Végétales appliquées aux Plantes Aromatiques et Médicinales (BVPAM), and Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Neurons, MESH: Anoxia, MESH: Rats, Sprague-Dawley, Supraoptic nucleus, MESH: Charcoal, Hypercapnia, Rats, Sprague-Dawley, 0302 clinical medicine, Neural Pathways, MESH: Renal Dialysis, MESH: Animals, MESH: Chemoreceptors, Hypoxia, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Neurons, 0303 health sciences, MESH: Kidney, Artificial, MESH: Proto-Oncogene Proteins c-fos, General Neuroscience, MESH: Aluminum, Solitary tract, Immunohistochemistry, Chemoreceptor Cells, medicine.anatomical_structure, Hypothalamus, Respiratory Physiological Phenomena, Brainstem, Proto-Oncogene Proteins c-fos, circulatory and respiratory physiology, medicine.medical_specialty, MESH: Rats, Central nervous system, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, Medulla, MESH: Respiratory Physiology, 030304 developmental biology, MESH: Neural Pathways, MESH: Immunohistochemistry, MESH: Hypothalamus, Pons, Rats, Endocrinology, nervous system, MESH: Hypercapnia, MESH: Oxides, MESH: Brain Stem, Neurology (clinical), MESH: Adsorption, Neuroscience, Nucleus, 030217 neurology & neurosurgery, Brain Stem, Developmental Biology
Abstract: The adaptation to hypoxia and hypercapnia requires the activation of several anatomical structures along the neuraxis. In this study, using Fos immunoreactivity, we sought to map neuronal populations involved in chemoreflex networks activated during the responses to moderate hypoxia (O(2) 11%), and hypercapnia (CO(2) 5%) in the brainstem and the hypothalamus of the rat. In the medulla, hypoxia elicited marked and significant staining in the nucleus of the solitary tract (NTS), and in parapyramidal neurons located near the ventral surface, whereas hypercapnia evoked significantly c-fos only near the ventral surface in paraolivar neurons. In contrast, within pontine and suprapontine structures, both hypoxia and hypercapnia evoked similarly Fos immunoreactivity in the lateral parabrachialis area, the central grey, the caudal hypothalamus (dorsomedial and posterior hypothalamic nuclei), and in a ventro-lateral hypothalamic area, extending from the rostral limit of the mammillary nuclei to the retrochiasmatic area. More rostrally, labelling was observed in the paraventricular nucleus of the hypothalamus in response to hypercapnia, and in the supraoptic nucleus in response to hypoxia. These results support the hypothesis that chemoreflexes pathways are not only restricted to medulla and pons but also involved mesencephalic and hypothalamic regions. The parabrachialis area and the central grey may be key relays between caudal and ventral hypothalamic neurons, and medullary neurons involved in the response to hypoxia and hypercapnia.
Published: 2000

27. The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions

Author: Chartrel, C, Alvear-Perez, P, Iturrioz, X., Reaux-Le Goazigo, A., Audinot, V., Chomarat, C, Coge, C, Nosjean, O., Rodriguez, M., Galizzi, J., Goazigo, R., Chomarat, P., Coge, F., Chartrel, Nicolas, Alonzeau, Jessy, Alexandre, David, Jeandel, Jean, Alvear-Perez, Rodrigo, Leprince, Jérôme, Boutin, Jean, Vaudry, Hubert, Anouar, Youssef, Llorens-Cortes, Catherine, Jeandel, Lydie, Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Institut de Recherches Servier, Centre de Recherches de Croissy, Centre interdisciplinaire de recherche en biologie (CIRB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, Receptors, G-Protein-Coupled, 0302 clinical medicine, MESH: Pituitary Gland, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Ligands, MESH: Animals, Tissue Distribution, Receptor, Peptide sequence, MESH: Vertebrates, MESH: Cyclic AMP, 0303 health sciences, Vertebrate, Cell biology, Hypothalamus, Vertebrates, medicine.medical_specialty, MESH: Ghrelin, Neuropeptide, Biology, Models, Biological, 03 medical and health sciences, Neuroendocrine Cells, biology.animal, Internal medicine, medicine, MESH: Neuroendocrine Cells, MESH: Protein Binding, Animals, Humans, Amino Acid Sequence, MESH: Tissue Distribution, Gene, 030304 developmental biology, G protein-coupled receptor, MESH: Humans, MESH: Molecular Sequence Data, Endocrine and Autonomic Systems, MESH: Transfection, Neuropeptides, QRFP, MESH: Models, Biological, Endocrinology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Peptide Hormones, 030217 neurology & neurosurgery
Abstract: International audience; Identification of novel neuropeptides and their cognate G protein-coupled receptors is essential for a better understanding of neuroendocrine regulations. The RFamide peptides represent a family of regulatory peptides that all possess the Arg-Phe-NH2 motif at their C-terminus. In mammals, seven RFamide peptides encoded by five distinct genes have been characterized. The present review focuses on 26RFa (or QRFP) which is the latest member identified in this family. 26RFa is present in all vertebrate phyla and its C-terminal domain (KGGFXFRF-NH2), which is responsible for its biological activity, has been fully conserved during evolution. 26RFa is the cognate ligand of the orphan G protein-coupled receptor GPR103 that is also present from fish to human. In all vertebrate species studied so far, 26RFa-expressing neurons show a discrete localization in the hypothalamus, suggesting important neuroendocrine activities for this RFamide peptide. Indeed, 26RFa plays a crucial role in the control of feeding behavior in mammals, birds and fish. In addition, 26RFa up-regulates the gonadotropic axis in mammals and fish. Finally, evidence that the 26RFa/GPR103 system regulates steroidogenesis, bone formation, nociceptive transmission and arterial blood pressure has also been reported. Thus, 26RFa appears to act as a key neuropeptide in vertebrates controlling vital neuroendocrine functions. The pathophysiological implication of the 26RFa/GPR103 system in human is totally unknown and some fields of investigation are proposed.
Published: 2010

28. Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking

Author: Laurent Muller, Jean-Marie Gasc, Maud Clemessy, Daniel Bur, Marie-Claire Gubler, Olivier Gribouval, Xavier Iturrioz, Pierre Corvol, Annie Michaud, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paul Verlaine - Metz (UPVM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Angiogénèse embryonnaire et pathologique, Iturrioz, Xavier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, [SDV]Life Sciences [q-bio], Mutant, medicine.disease_cause, Kidney Tubules, Proximal, 0302 clinical medicine, Pregnancy, Cricetinae, Gene duplication, [CHIM] Chemical Sciences, Renin, Missense mutation, Genetics (clinical), Cellular localization, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Mutation, General Medicine, Recombinant Proteins, 3. Good health, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], Protein Transport, Female, medicine.medical_specialty, Molecular Sequence Data, CHO Cells, Biology, Cell Line, 03 medical and health sciences, Cricetulus, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Renin–angiotensin system, Genetics, medicine, [CHIM]Chemical Sciences, Animals, Humans, Point Mutation, Amino Acid Sequence, Molecular Biology, Loss function, 030304 developmental biology, Point mutation, Protein Structure, Tertiary, Endocrinology, Urogenital Abnormalities, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized by persistent fetal anuria and perinatal death. During the systematic screening of mutations of the different genes of the renin-angiotensin system associated with RTD, two missense mutations in the renin gene were previously identified, the first affects one of the two catalytic aspartates (D38N) of renin, and the second, S69Y, is located upstream of the 'flap', a mobile β-hairpin structure which covers the substrate-binding site of renin. Here we report a novel renin mutation leading to the duplication of the tyrosine residue Y15dup, homologous to Y9 in some other aspartyl proteases, which seems to play a crucial role along the activation pathway. The biochemical and cellular mechanisms underlying renin inactivation were investigated. We expressed prorenin constructs harboring the identified point mutations in two established cell lines, able (AtT-20 cells) or unable (CHO cells) to process prorenin to renin and we evaluated the cellular localization of renin mutants and their functional properties. All three mutants were misfolded to different levels, were enzymatically inactive and exhibited abnormal intracellular trafficking. We suggest a misfolding of Y15dup renin, a partial misfolding of D38N prorenin and a misfolding of S69Y prorenin leading to complete absence of secretion. The structural consequences of the renin mutations were estimated by molecular modeling, which suggested some important structural alterations. This is the first characterization of the mechanisms underlying loss of renin function in RTD.
Published: 2010

29. By Interacting with the C-terminal Phe of Apelin, Phe 255 and Trp 259 in Helix VI of the Apelin Receptor Are Critical for Internalization

Author: Rodrigo Alvear-Perez, Xavier Iturrioz, Catherine Llorens-Cortes, Vincent Leroux, Romain Gerbier, Bernard Maigret, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Collaboration C. Llorens-Cortes, Collège de France, ANR-05-PCOD-0001,APELIN,L'APELINE UNE CIBLE THERAPEUTIQUE POTENTIELLE DANS LE TRAITEMENT DE L'INSUFFISANCE CARDIAQUE : DU DEVELOPPEMENT DE LA MOLECULE A L'INVESTIGATION CLINIQUE.(2005), Iturrioz, Xavier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR: Apelin,Apelin, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP)
Subjects: Models, Molecular, Protein Conformation, [SDV]Life Sciences [q-bio], Phenylalanine -- metabolism, Biochemistry, Receptors, G-Protein-Coupled, Radioligand Assay, 0302 clinical medicine, Protein structure, Cricetinae, [CHIM] Chemical Sciences, Cyclic AMP, Internalization, Receptor, ComputingMilieux_MISCELLANEOUS, media_common, Apelin Receptors, 0303 health sciences, biology, Chemistry, Receptors, G-Protein-Coupled -- genetics -- metabolism, Tryptophan, Recombinant Fusion Proteins -- genetics -- metabolism, Sciences bio-médicales et agricoles, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Cell biology, Apelin, [SDV] Life Sciences [q-bio], Protein Structure and Folding, Intercellular Signaling Peptides and Proteins, Receptor Structure-Function, Cricetulus, Intercellular Signaling Peptides and Proteins -- chemistry -- genetics -- metabolism, Signal transduction, Sciences exactes et naturelles, Computer Modeling, Signal Transduction, Phenylalanine, Recombinant Fusion Proteins, media_common.quotation_subject, Molecular Sequence Data, CHO Cells, 03 medical and health sciences, Animals, Humans, [CHIM]Chemical Sciences, Amino Acid Sequence, Binding site, Site-directed Mutagenesis, Tryptophan -- metabolism, Molecular Biology, 030304 developmental biology, Apelin receptor, Cell Biology, biology.organism_classification, Rats, Mutagenesis, Site-Directed, Cyclic AMP -- metabolism, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Peptides, G Protein-coupled Receptors (GPCR), 030217 neurology & neurosurgery
Abstract: Apelin is the endogenous ligand of the orphan seven-transmembrane domain (TM) G protein-coupled receptor APJ. Apelin is involved in the regulation of body fluid homeostasis and cardiovascular functions. We previously showed the importance of the C-terminal Phe of apelin 17 (K17F) in the hypotensive activity of this peptide. Here, we show either by deleting the Phe residue (K16P) or by substituting it by an Ala (K17A), that it plays a crucial role in apelin receptor internalization but not in apelin binding or in Gα(i)-protein coupling. Then we built a homology three-dimensional model of the human apelin receptor using the cholecystokinin receptor-1 model as a template, and we subsequently docked K17F into the binding site. We visualized a hydrophobic cavity at the bottom of the binding pocket in which the C-terminal Phe of K17F was embedded by Trp(152) in TMIV and Trp(259) and Phe(255) in TMVI. Using molecular modeling and site-directed mutagenesis studies, we further showed that Phe(255) and Trp(259) are key residues in triggering receptor internalization without playing a role in apelin binding or in Gα(i)-protein coupling. These findings bring new insights into apelin receptor activation and show that Phe(255) and Trp(259), by interacting with the C-terminal Phe of the pyroglutamyl form of apelin 13 (pE13F) or K17F, are crucial for apelin receptor internalization., info:eu-repo/semantics/published
Published: 2010

30. Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist

Author: Xavier Iturrioz, Hadjila Chabane, Nadia De Mota, Alain Berdeaux, Marcel Hibert, Dominique Bonnet, Vincent Leroux, Bernard Maigret, Melissande Le Jouan, Hubert Dabiré, Rodrigo Alvear-Perez, Jean-Luc Galzi, Fabrice Guillier, Catherine Llorens-Cortes, Romain Gerbier, Christel Anne Franchet, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Collaboration C. Llorens-Cortes, Collège de France, ANR-08-PCVI-0035,APELINE,Développement d'agonistes et d'antagonistes du récepteur de l'apéline(2008), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Intégrité du génome, Ecole Supérieure de Biotechnologie de Strasbourg (ESBS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Iturrioz, Xavier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR: Apeline,Apeline
Subjects: Male, Vasopressin, [SDV]Life Sciences [q-bio], Drug Evaluation, Preclinical, Pharmacology, Rats, Inbred WKY, Biochemistry, Receptors, G-Protein-Coupled, Mice, 0302 clinical medicine, Aquaretic, [CHIM] Chemical Sciences, Cyclic AMP, Fluorescence Resonance Energy Transfer, Receptor, Internalization, Aorta, media_common, Apelin Receptors, 0303 health sciences, Chemistry, Dipeptides, Fluoresceins, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Apelin, [SDV] Life Sciences [q-bio], Vasodilation, Biotechnology, Agonist, medicine.medical_specialty, Vasopressins, medicine.drug_class, media_common.quotation_subject, Partial agonist, 03 medical and health sciences, Internal medicine, Genetics, medicine, Animals, Humans, [CHIM]Chemical Sciences, Molecular Biology, 030304 developmental biology, Apelin receptor, Colforsin, Rats, Endocrinology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery
Abstract: International audience; Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To explore further upstream the role played by this peptide, nonpeptidic agonists and antagonists of the apelin receptor are required. To identify such compounds that do not exist to date, we used an original fluorescence resonance energy transfer-based assay to screen a G-protein-coupled receptor-focused library of fluorescent compounds on the human EGFP-tagged apelin receptor. This led to isolated E339-3D6 that displayed a 90 nM affinity and behaved as a partial agonist with regard to cAMP production and as a full agonist with regard to apelin receptor internalization. Finally, E339-3D6 induced vasorelaxation of rat aorta precontracted with noradrenaline and potently inhibited systemic vasopressin release in water-deprived mice when intracerebroventricularly injected. This compound represents the first nonpeptidic agonist of the apelin receptor, the optimization of which will allow development of a new generation of vasodilator and aquaretic agents.
Published: 2010

31. Multiple cross talk between angiotensin II, bradykinin, and insulin signaling in the cortical thick ascending limb of rat kidney

Author: Xavier Iturrioz, Annette Hus-Citharel, Catherine Llorens-Cortes, Nadine Bouby, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Iturrioz, Xavier
Subjects: Male, medicine.medical_specialty, Pyridines, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Blotting, Western, Angiotensin II Type 2 Receptor Blockers, In Vitro Techniques, Bradykinin, Kidney, Receptor tyrosine kinase, Rats, Sprague-Dawley, Endocrinology, Internal medicine, [CHIM] Chemical Sciences, Bradykinin B2 Receptor Antagonists, medicine, [CHIM]Chemical Sciences, Animals, Insulin, Receptor, biology, Angiotensin II, Imidazoles, Rats, [SDV] Life Sciences [q-bio], Insulin receptor, biology.protein, cardiovascular system, Calcium, Signal transduction, Tyrosine kinase, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract: Cortical thick ascending limb (CTAL) naturally expresses the angiotensin II (AngII) receptor type 1A (AT(1)-R), the bradykinin (BK) receptor type 2 (B(2)-R), and the insulin receptor. This segment is made of a single morphologically distinct cell type. AngII and BK are involved in same transduction pathways but differ markedly in their physiological actions on Na(+) transport. Besides, the insulin signaling intersects with those of AngII and BK at multiple levels and especially by stimulation on Na(+) reabsorption. Thus, the CTAL is a biologically suitable model to study the cross talk between G protein-coupled receptors or G protein-coupled receptors and receptor tyrosine kinase. In this work, the cross talks between AngII, BK, and insulin signaling are studied in rat CTAL by measuring changes in [Ca(2+)](i). We show that BK exerts negative modulatory effects on AngII-induced [Ca(2+)](i) responses dependent on tyrosine kinase and MAPK pathways. Moreover, in the presence of BK, AngII-induced Na(+) transport is suppressed. These effects suggest an interaction between AT(1)-R and B(2)-R. We show a positive interaction between the insulin receptor and the AT(1)-R through a protein kinase A-dependent mechanism that involves MAPK cascade, leading to the stimulation of the Ca(2+) influx induced by AngII. The presence of such interactions brings additional arguments for a complex and fine regulation of CTAL functions and puts forward the potentially beneficial effect of BK across this segment, in case of hyperinsulinemia or insulin resistance, by its negative feedback on AngII actions.
Published: 2010

32. Acute food deprivation reduces expression of diazepam-binding inhibitor, the precursor of the anorexigenic octadecaneuropeptide ODN, in mouse glial cells

Author: Schouft, Marie-Thérèse, Fontaine, Marc, Scalbert, Elisabeth, Malagon, Maria, Gandolfo, Pierrick, Desrues, Laurence, Cellier, Eric, Decker, Annick, Clerens, Stefan, Vandesande, Frans, Do-Rego, C., Beauvillain, C., Baroncini, Marc, Balment, Richard, Dujardin, Cynthia, Tollemer, Helene, BRUZZONE, FEDERICA, Tollemer, Hélène, Do-Régo, Jean, Simonnet, Guy, VALLARINO, MAURO, Beauvillain, Jean, Costentin, Jean, Do-Régo, Jean-Claude, Beauvillain, Jean-Claude, Chartrel, C, Alvear-Perez, P, Iturrioz, X., Reaux-Le Goazigo, A., Audinot, V., Chomarat, C, Coge, C, Nosjean, O., Rodriguez, M., Galizzi, J., Goazigo, R., Chomarat, P., Coge, F., Chartrel, Nicolas, Alonzeau, Jessy, Alexandre, David, Jeandel, Jean, Alvear-Perez, Rodrigo, Boutin, Jean, Anouar, Youssef, Llorens-Cortes, Catherine, Jeandel, Lydie, Carlier, Ludovic, Ségalas-Milazzo, Isabelle, Guilhaudis, Laure, Oulyadi, Hassan, Davoust, Daniel, Dubessy, Christophe, Scalbert, Elizabeth, Pfeiffer, Bruno, Renard, Pierre, Lihrmann, Isabelle, Pacaud, Pierre, Chevrier, Lucie, De Brevern, Alexandre, Hernandez, Eva, Guedj, Anne Marie, de Roux, Nicolas, Cholez, V, Debuysscher, V, Bourgeais, B, Boudot, B, Tron, F., Brassart, B., Regnier, A., Bissac, E, Pecnard, E, Gouilleux, F., Lassoued, K, Gouilleux-Gruart, V, Cholez, E, Bourgeais, J, Boudot, C., Gouilleux, V, Chuquet, Julien, Lecrux, Clotilde, Chatenet, David, Chazalviel, Laurent, Roussel, Simon, MacKenzie, Eric, Touzani, Omar, Tonon, M.C, Li, S., Leprince, J�r�me, Tonon, M.C., Compère, M, Lanfray, D, Castel, Hélène, Morin, M., Leprince, Jérôme, Dureuil, B, Vaudry, Hubert, Pelletier, G., Tonon, Marie-Christine, Compère, V., Morin, F., Dureuil, D, Vaudry, V, inconnu, Inconnu, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Chercheur indépendant, Laboratoire de l'intégration, du matériau au système (IMS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, University of Córdoba [Córdoba], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, UMR 5287, Homéostasie-Allostasie-Pathologie-Réhabilitation, Centre National de la Recherche Scientifique (CNRS), Neuropsycho-pharmacologie expérimentale, Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Servier, Centre de Recherches de Croissy, ESPE de l'Académie d'Amiens, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Université Henri Poincaré - Nancy 1 (UHP), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatique génomique et moléculaire ((U 726)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service des Maladies Métaboliques et Endocriniennes, Hôpital Universitaire Carémeau [Nîmes], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Henri Becquerel-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), STMicroelectronics, Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et régulations cellulaires (MERC), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Neurodégénérescence : modèles et stratégies thérapeutiques (NMST), Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), IRCELYON-Ingéniérie, du matériau au réacteur (ING), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Télécom SudParis (TSP), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Rouen, Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université Le Havre Normandie (ULH), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Leptin, Male, Transcription, Genetic, MESH: Sequence Homology, Amino Acid, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, Energy homeostasis, MESH: Down-Regulation, MESH: Ependyma, Mice, 0302 clinical medicine, Endocrinology, Lateral Ventricles, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Insulin, MESH: Animals, MESH: Proline-Rich Protein Domains, MESH: Peptide Fragments, MESH: Lateral Ventricles, Diazepam Binding Inhibitor, 2. Zero hunger, 0303 health sciences, MESH: Ranidae, MESH: Receptors, Kisspeptin-1, Fasting, medicine.anatomical_structure, Hypothalamus, Neuroglia, MESH: Neuroglia, Ependyma, Diazepam binding inhibitor, Injections, Intraperitoneal, MESH: Injections, Intraperitoneal, Protein Binding, MESH: Protein Transport, medicine.medical_specialty, MESH: Rats, Central nervous system, Down-Regulation, Neuropeptide, MESH: Fasting, MESH: Insulin, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, MESH: Protein Binding, Molecular Biology, MESH: Mice, Third Ventricle, MESH: RNA, Messenger, 030304 developmental biology, MESH: Transcription, Genetic, Neuropeptides, MESH: Time Factors, MESH: Rats, Wistar, MESH: Leptin, MESH: Hypothalamus, Peptide Fragments, MESH: Male, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Diazepam Binding Inhibitor, 030217 neurology & neurosurgery, MESH: Third Ventricle
Abstract: In the central nervous system of mammals, the gene encoding diazepam-binding inhibitor (DBI) is exclusively expressed in glial cells. Previous studies have shown that central administration of a DBI processing product, the octadecaneuropeptide ODN, causes a marked inhibition of food consumption in rodents. Paradoxically, however, the effect of food restriction on DBI gene expression has never been investigated. Here, we show that in mice, acute fasting dramatically reduces DBI mRNA levels in the hypothalamus and the ependyma bordering the third and lateral ventricles. I.p. injection of insulin, but not of leptin, selectively stimulated DBI expression in the lateral ventricle area. These data support the notion that glial cells, through the production of endozepines, may relay peripheral signals to neurons involved in the central regulation of energy homeostasis.
Published: 2010

33. Identification and Characterization of E339-3D6, the First Nonpeptidic Apelin Receptor Agonist XAVIER ITURRIOZ

Author: Itturioz, Xavier, Alvear-Perez, Rodrigo, de Mota, Nadia, Franchet, Christel, Guillier, Fabrice, Leroux, Vincent, Dabire, Hubert, Le Jouan, Melissande, Chabane, Hadjila, Gerbier, Romain, Bonnet, Dominique, Berdeaux, Alain, Maigret, Bernard, Galzi, J.-L, Hibert, Marcel, Llorens-Cortes, Catherine, vinauger, michele, INSERM U691 - Collège de France (INSERM ), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Centre National de la Recherche Scientifique (CNRS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), INSERM U691 - Collège de France, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV]Life Sciences [q-bio], [CHIM] Chemical Sciences, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [CHIM]Chemical Sciences, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2010

34. Identification of threonine 348 as a residue involved in aminopeptidase A substrate specificity

Author: Cédric Claperon, Raphael Rozenfeld, Bernard Maigret, Catherine Llorens-Cortes, Xavier Iturrioz, Inmaculada Banegas-Font, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Llorens Cortes, Catherine
Subjects: Threonine, Angiotensin III, Molecular Conformation, MESH: Cricetinae, MESH: Receptors, G-Protein-Coupled, Biochemistry, MESH: Radioligand Assay, Substrate Specificity, Serine, MESH: Receptors, Ghrelin, MESH: Recombinant Proteins, Mice, chemistry.chemical_compound, 0302 clinical medicine, Glutamates, MESH: RNA, Small Interfering, MESH: Microscopy, Confocal, MESH: Animals, Tyrosine, MESH: Threonine, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Glutamyl Aminopeptidase, 0303 health sciences, Molecular Structure, Enzyme Catalysis and Regulation, biology, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Recombinant Proteins, MESH: Mutagenesis, Site-Directed, MESH: Calcium, MESH: Receptor, Adenosine A2B, Stereochemistry, MESH: RNA Interference, MESH: Molecular Structure, Organophosphonates, MESH: Phosphonic Acids, MESH: Receptor, Adenosine A3, Glutamyl Aminopeptidase, 03 medical and health sciences, MESH: Glutamates, MESH: CHO Cells, Animals, MESH: Protein Binding, MESH: Blotting, Western, Carboxylate, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Molecular Conformation, MESH: Humans, MESH: Transfection, Active site, Cell Biology, MESH: Kidney, MESH: Arvicolinae, MESH: Adenosine, Angiotensin II, MESH: Cell Line, chemistry, Glutamyl aminopeptidase, Mutagenesis, Site-Directed, biology.protein, Calcium, MESH: Substrate Specificity, 030217 neurology & neurosurgery
Abstract: International audience; Aminopeptidase A (APA; EC 3.4.11.7) is a membrane-bound zinc metalloprotease cleaving in the brain the N-terminal aspartyl residue of angiotensin II to generate angiotensin III, which exerts a tonic stimulatory effect on the central control of blood pressure in hypertensive animals. We docked the specific APA inhibitor, glutamate phosphonate, in the three-dimensional model of the mouse APA ectodomain in the presence of Ca(2+). In the S1 subsite of this model, the Ca(2+) atom was coordinated with Asp-213, Asp-218,y and Glu-215 and three water molecules, one of which formed a hydrogen bond with the carboxylate side chain of the inhibitor. We report here that the carboxylate side chain of glutamate phosphonate also formed a hydrogen bond with the alcohol side chain of Thr-348. Mutagenic replacement of Thr-348 with an aspartate, tyrosine, or serine residue led to a modification of the hydrolysis velocity, with no change in the affinity of the recombinant enzymes for the substrate GluNA, either in the absence or presence of Ca(2+). In the absence of Ca(2+), the mutations modified the substrate specificity of APA, which was nevertheless restored by the addition of Ca(2+). An analysis of three-dimensional models of the corresponding Thr-348 mutants revealed that the interaction between this residue and the inhibitor was abolished or disturbed, leading to a change in the position of the inhibitor in the active site. These findings demonstrate a key role of Thr-348 in substrate specificity of APA for N-terminal acidic amino acids by insuring the optimal positioning of the substrate during catalysis.
Published: 2009

35. Asp218 participates with Asp213 to bind a Ca2+ atom into the S1 subsite of aminopeptidase A: a key element for substrate specificity

Author: Bernard Maigret, Xavier Iturrioz, Mayumi Okada, Nicolas Inguimbert, Catherine Llorens-Cortes, Bernard P. Roques, Cédric Claperon, Raphael Rozenfeld, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Pharmacologie Chimique et Génétique ( UPCG - UMR_S 640/UMR 8151 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ), Knowledge representation, reasonning ( ORPAILLEUR ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université Henri Poincaré - Nancy 1 ( UHP ) -Université Nancy 2-Institut National Polytechnique de Lorraine ( INPL ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Henri Poincaré - Nancy 1 ( UHP ) -Université Nancy 2-Institut National Polytechnique de Lorraine ( INPL ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Iturrioz, Xavier, and Llorens Cortes, Catherine
Subjects: Models, Molecular, MESH : Glutamyl Aminopeptidase, MESH : Glutamates, MESH: Amino Acids, [SDV]Life Sciences [q-bio], Angiotensin III, monozinc aminopeptidase, MESH : Aspartic Acid, MESH: Cricetinae, MESH: Amino Acid Sequence, Biochemistry, MESH: Aspartic Acid, Substrate Specificity, MESH : Sulfhydryl Compounds, Mice, chemistry.chemical_compound, Glutamates, MESH: Cricetulus, Cricetinae, [CHIM] Chemical Sciences, MESH : CHO Cells, MESH: Animals, Amino Acids, Enzyme Inhibitors, Site-directed mutagenesis, inhibitor design, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [PHYS]Physics [physics], MESH: Glutamyl Aminopeptidase, 0303 health sciences, MESH : Substrate Specificity, MESH: Kinetics, Hydrogen bond, MESH : Amino Acid Sequence, 030302 biochemistry & molecular biology, MESH : Cricetinae, Life Sciences, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Phosphonate, MESH : Mutagenesis, Site-Directed, molecular modelling, [SDV] Life Sciences [q-bio], MESH: Mutagenesis, Site-Directed, Ectodomain, MESH: Enzyme Inhibitors, MESH: Calcium, Pharmacophore, MESH : Kinetics, site-directed mutagenesis, MESH : Phosphonic Acids, MESH: Models, Molecular, calcium-binding site, hypertension, Stereochemistry, MESH : Models, Molecular, education, MESH : Cricetulus, Organophosphonates, MESH: Phosphonic Acids, CHO Cells, Glutamyl Aminopeptidase, 03 medical and health sciences, Cricetulus, MESH: Glutamates, site directed mutagenesis, MESH: CHO Cells, MESH : Mice, Animals, [CHIM]Chemical Sciences, Amino Acid Sequence, Sulfhydryl Compounds, Carboxylate, calcium binding site, MESH : Calcium, MESH: Sulfhydryl Compounds, Molecular Biology, MESH: Mice, 030304 developmental biology, Aspartic Acid, MESH : Enzyme Inhibitors, Binding Sites, molecular modeling, Rational design, Cell Biology, Kinetics, chemistry, MESH: Binding Sites, Mutagenesis, Site-Directed, Calcium, MESH : Amino Acids, MESH: Substrate Specificity, MESH : Animals, MESH : Binding Sites
Abstract: International audience; APA (aminopeptidase A; EC 3.4.11.7) is a membrane-bound zinc metallopeptidase, also activated by Ca(2+), involved in the formation of brain angiotensin III, which exerts a tonic stimulatory action on the central control of blood pressure in hypertensive animals. In the present study, in the three-dimensional model of the ectodomain of mouse APA, we docked the specific APA inhibitor glutamate phosphonate, in the presence of Ca(2+). The model showed the presence of one Ca(2+) atom in an hydrophilic pocket corresponding to the S1 subsite in which the lateral chain of the inhibitor is pointing. In this pocket, the Ca(2+) atom was hexaco-ordinated with the acidic side chains of Asp(213) and Asp(218), the carbonyl group of Glu(215) and three water molecules, one of them being engaged in a hydrogen bond with the negatively charged carboxylate side chain of the inhibitor. Mutagenic replacement of Asp(213) and Asp(218) with a conservative residue maintained the ability of mutated APAs to be activated by Ca(2+). However, the replacement by a non-conservative residue abolished this property, demonstrating the crucial role of these residues in Ca(2+) binding. We also showed the involvement of these residues in the strict specificity of APA in the presence of Ca(2+) for N-terminal acidic residues from substrates or inhibitors, since mutagenic replacement of Asp(213) and Asp(218) induced a decrease of the inhibitory potencies of inhibitors homologous with acidic residues. Finally, this led to the rational design of a new potent APA inhibitor, NI926 (K(i)=70 nM), which allowed us to precisely localize Asp(213) at the entrance and Asp(218) at the bottom of the S1 subsite. Taken together, these data provide new insight into the organization and functional role of the APA S1 subsite and will allow the design of pharmacophore of the inhibitor, helpful for the development of a new generation of APA inhibitors as central-acting antihypertensive agents.
Published: 2008

36. Aminopeptidase A inhibitors as centrally acting antihypertensive agents

Author: Yannick Marc, Catherine Llorens-Cortes, Laurence Bodineau, Cédric Claperon, Alain Frugière, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Llorens Cortes, Catherine
Subjects: medicine.medical_specialty, Angiotensin III, 030204 cardiovascular system & hematology, Pharmacology, Glutamyl Aminopeptidase, Models, Biological, MESH: Hypertension, Renin-Angiotensin System, 03 medical and health sciences, 0302 clinical medicine, Aminopeptidase A, In vivo, MESH: Renin-Angiotensin System, Internal medicine, Renin–angiotensin system, medicine, Animals, MESH: Animals, MESH: Disulfides, Disulfides, Enzyme Inhibitors, Receptor, Antihypertensive Agents, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, chemistry.chemical_classification, MESH: Glutamyl Aminopeptidase, 0303 health sciences, MESH: Antihypertensive Agents, Effector, business.industry, Angiotensin II, MESH: Models, Biological, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Endocrinology, Blood pressure, Enzyme, chemistry, MESH: Enzyme Inhibitors, Hypertension, MESH: Sulfonic Acids, MESH: Angiotensin II, Sulfonic Acids, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; Among the main bioactive peptides of the brain renin-angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for the type 1 and type 2 Ang receptors. Both peptides, injected intracerebroventricularly, cause similar increase in blood pressure (BP). Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarized recent insights into the predominant role of brain AngIII in the central control of BP underlining the fact that brain aminopeptidase A (APA), the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension. This led to the development of potent, systematically active APA inhibitors, such as RB150, as a prototype of a new class of centrally acting antihypertensive agents for the treatment of certain forms of hypertension.
Published: 2008

37. Opposite potentiality of hypothalamic coexpressed neuropeptides, apelin and vasopressin in maintaining body-fluid homeostasis

Author: Catherine Llorens-Cortes, Françoise Moos, Université Pierre et Marie Curie - Paris 6 (UPMC), Psychoneuroimmunologie, nutrition et génétique, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux Ségalen [Bordeaux 2], Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Psychoneuroimmunologie, Nutrition et Génétique (PsyNuGen), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Llorens Cortes, Catherine, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Vasopressin, MESH: Sequence Homology, Amino Acid, [SDV]Life Sciences [q-bio], VASOPRESSIN, Blood Pressure, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, MESH: Neuropeptides, Ligands, Receptors, G-Protein-Coupled, MESH: Body Fluids, Mice, 0302 clinical medicine, Arginine vasopressin receptor 2, MESH: Ligands, Homeostasis, MESH: Animals, Conserved Sequence, Vasopressin receptor, Arginine vasopressin receptor 1B, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Apelin Receptors, MESH: Conserved Sequence, MESH: Blood Pressure, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin, Body Fluids, MESH: Homeostasis, WATER BALANCE, Intercellular Signaling Peptides and Proteins, MESH: Vasopressins, hormones, hormone substitutes, and hormone antagonists, NEUROPEPTIDES COLOCALIZATION, medicine.medical_specialty, MESH: Rats, Vasopressins, Molecular Sequence Data, Hypothalamus, Neuropeptide, MESH: Carrier Proteins, Biology, 03 medical and health sciences, Adipokines, Internal medicine, medicine, Animals, Humans, Amino Acid Sequence, DIURESIS, MESH: Intercellular Signaling Peptides and Proteins, MESH: Mice, 030304 developmental biology, Apelin receptor, MESH: Molecular Sequence Data, MESH: Humans, Sequence Homology, Amino Acid, Neuropeptides, MESH: Hypothalamus, Rats, Endocrinology, nervous system, Magnocellular cell, ANTIDIURESIS, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: International audience; This review concentrates on the characteristics and functionality of endocrine neurons in the hypothalamo-neurohypophysial system, coexpressing two peptides, vasopressin and apelin. Vasopressin is synthesized in the soma of magnocellular neurons, then packaged in granules with its respective receptors. In these neurons, apelin is generated from a larger precursor proapelin and is detected in vesicles, some of them colocalize with vasopressin, for others there is a marked segregation of apelin and vasopressin immunoreactivity along the hypothalamo-hypophyseal axons. Furthermore, apelin receptors, like V1a-type and V1b-type vasopressin receptors, are synthesized by magnocellular vasopressin neurons. In lactating rodents, apelin given intracerebroventricularly inhibited the phasic electrical activity of vasopressin neurons, reduced plasma vasopressin levels and increased aqueous diuresis, showing that apelin acts as a potent diuretic neuropeptide, counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Moreover, in response to potent physiological stimuli known to evoke increased phasic activity of vasopressin neurons (hyper-osmolarity like during dehydration), both the soma dendrites and neurohypophysial terminals loose their dense staining quality, and vasopressin is released by (i) dendrites in the extracellular space to optimize the characteristic phasic activity necessary to a sustained release of vasopressin and (ii) by terminals in blood circulation where vasopressin then ensures its main endocrine actions at kidney level (antidiuretic effect). Conversely, apelin accumulates in these neurons rather than being released into the bloodstream and probably into the nuclei. Thus, decreases in the local supply of apelin to magnocellular vasopressin cell bodies may facilitate the expression by vasopressin neurons of an optimized phasic activity, by decreasing the inhibitory actions of apelin on these neurons. Antagonistic regulation of apelin and vasopressin has a biological purpose, making it possible to maintain the water balance of the organism by preventing additional water loss via kidneys. This reveals a new physiological concept of dual and opposite functional potentiality for endocrine neurons coexpressing different neuropeptides in separate vesicles: depending on the degree of their electrical activation/inhibition, neurons release selectively the very coexpressed peptides that will ensure its accurate endocrine functions in perfect accordance with the hormonal demand.
Published: 2008

38. Effect of apelin on glomerular hemodynamic function in the rat kidney

Author: Annette Hus-Citharel, Catherine Llorens-Cortes, Laurence Bodineau, Nadine Bouby, Jean-Marie Gasc, Alain Frugière, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Llorens Cortes, Catherine, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Afferent arterioles, Vascular smooth muscle, MESH : RNA, Messenger, MESH : Myocytes, Smooth Muscle, Kidney Glomerulus, MESH : Receptors, Cell Surface, MESH : Arterioles, vascular regulation, Vasodilation, glomerulus, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Rats, Sprague-Dawley, MESH : Vasodilation, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH: Animals, MESH : Female, Receptor, MESH: Receptors, Cell Surface, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH : Diuresis, MESH : Hemodynamics, MESH : Rats, Angiotensin II, MESH: Diuresis, MESH: Myocytes, Smooth Muscle, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin, Arterioles, medicine.anatomical_structure, MESH : Nitric Oxide, Nephrology, Intercellular Signaling Peptides and Proteins, MESH: Vasoconstriction, Female, MESH: Angiotensin II, MESH : Kidney Glomerulus, MESH : Vasoconstriction, MESH : Carrier Proteins, medicine.medical_specialty, MESH: Hemodynamics, MESH: Rats, MESH : Male, Myocytes, Smooth Muscle, MESH: Carrier Proteins, Receptors, Cell Surface, Nitric Oxide, Microcirculation, MESH : Angiotensin II, MESH: Vasodilation, 03 medical and health sciences, MESH: Arterioles, hemodynamic, Internal medicine, medicine, Animals, RNA, Messenger, 030304 developmental biology, Apelin receptor, MESH: RNA, Messenger, calcium, business.industry, Hemodynamics, MESH: Kidney Glomerulus, nephron, MESH: Male, MESH : Rats, Sprague-Dawley, Diuresis, Rats, MESH : Pregnancy, Endocrinology, Vasoconstriction, MESH: Nitric Oxide, MESH : Animals, business, Carrier Proteins, MESH: Female
Abstract: International audience; Apelin is a vasoactive peptide identified as the endogenous ligand of an orphan G protein-coupled receptor called APJ. Apelin and its receptor have been found in the brain and the cardiovascular system. Here we show that the apelin receptor mRNA is highly expressed in the glomeruli while its level of expression is lower in all nephron segments including collecting ducts that express vasopressin V2 receptors. Intravenous injection of apelin 17 into lactating rats induced a significant diuresis. Apelin receptor mRNA was also found in endothelial and vascular smooth muscle cells of glomerular arterioles. Apelin administration caused vasorelaxation of angiotensin II-preconstricted efferent and afferent arterioles as shown by an increase in their diameter. Activation of endothelial apelin receptors caused release of nitric oxide which inhibited angiotensin II-induced rise in intracellular calcium. In addition, it appears that apelin had a direct receptor-mediated vasoconstrictive effect on vascular smooth muscle. These results show that apelin has complex effects on the pre- and post glomerular microvasculature regulating renal hemodynamics. Its role on tubular function (if any) remains to be determined.
Published: 2008

39. Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

Author: Bodineau, Laurence, Marc, Yannick, Inguimbert, Nicolas, Fassot, Céline, Balavoine, Fabrice, Roques, Bernard, Llorens-Cortes, Catherine, Frugière, Alain, INSERM U691 - Collège de France (INSERM ), INSERM U640, Quantum Genomics, Fassot, Céline, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Abstract: International audience; Overactivity of the brain renin-angiotensin system has been implicated in the development and maintenance of hypertension. We reported previously that angiotensin II is converted to angiotensin III by aminopeptidase A in the mouse brain. We then used specific and selective aminopeptidase A inhibitors to show that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential candidate central nervous system target for the treatment of hypertension. Given this possible clinical use of aminopeptidase A inhibitors, it was, therefore, important to investigate their pharmacological activity after oral administration. We investigated RB150, a dimer of the selective aminopeptidase A inhibitor, EC33, generated by creating a disulfide bond. This chemical modification allows prodrug to cross the blood-brain barrier when administered by systemic route. Oral administration of RB150 in conscious DOCA-salt rats inhibited brain aminopeptidase A activity, resulting in values similar to those obtained with the brains of normotensive rats, demonstrating the central bioavailability of RB150. Oral RB150 treatment resulted in a marked dose-dependent reduction in blood pressure in DOCA-salt but not in normotensive rats, with an ED(50) in the 1-mg/kg range, achieved in
Published: 2008

40. Human brain aminopeptidase A: biochemical properties and distribution in brain nuclei

Author: Miklós Palkovits, Xavier Iturrioz, Laurence Bodineau, Catherine Llorens-Cortes, Céline Fassot, Cédric Claperon, Nadia De Mota, Bernard P. Roques, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuromorphological and Neuroendocrine Research Laboratory, Institute of Experimental Medicine [Budapest] (KOKI), Hungarian Academy of Sciences (MTA)-Hungarian Academy of Sciences (MTA), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Pharmacologie Chimique et Génétique ( UPCG - UMR_S 640/UMR 8151 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ), University Medical School and Hungarian Academy of Sciences, Llorens Cortes, Catherine, Semmelweis University of Medicine [Budapest], INSERM U640, Semmelweis University [Budapest], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), INSERM U691 - Collège de France (INSERM ), and Iturrioz, Xavier
Subjects: MESH : Glutamyl Aminopeptidase, Male, [SDV]Life Sciences [q-bio], MESH : Aged, MESH: Neurons, Blood Pressure, MESH : Microcirculation, Biochemistry, MESH: Hypertension, Mice, 0302 clinical medicine, [CHIM] Chemical Sciences, MESH: Microcirculation, MESH: Autonomic Pathways, MESH : Female, MESH: Animals, Autonomic Pathways, Enzyme Inhibitors, ComputingMilieux_MISCELLANEOUS, MESH: Evolution, Molecular, Nucleus ambiguus, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Aged, MESH: Glutamyl Aminopeptidase, Neurons, 0303 health sciences, MESH: Middle Aged, Solitary tract, MESH : Hypertension, Brain, Neurochemistry, Human brain, MESH: Blood Pressure, MESH : Adult, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypothalamus, MESH: Enzyme Inhibitors, Hypertension, Medulla oblongata, Female, MESH : Angiotensins, Adult, medicine.medical_specialty, MESH: Enzyme Activation, Angiotensins, Hypoglossal nucleus, MESH : Male, education, Biology, Glutamyl Aminopeptidase, MESH : Neurons, MESH: Neurochemistry, Evolution, Molecular, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Brain, Species Specificity, Internal medicine, MESH : Mice, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH : Blood Pressure, [CHIM]Chemical Sciences, MESH : Species Specificity, MESH: Species Specificity, Animals, Humans, MESH : Middle Aged, MESH : Evolution, Molecular, MESH: Mice, 030304 developmental biology, Aged, MESH : Autonomic Pathways, MESH : Enzyme Inhibitors, MESH: Humans, MESH: Angiotensins, Microcirculation, MESH : Humans, MESH: Adult, MESH: Male, Enzyme Activation, Endocrinology, Dorsal motor nucleus, MESH : Neurochemistry, MESH : Brain, MESH : Animals, MESH : Enzyme Activation, Nucleus, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Aminopeptidase A (APA) generated brain angiotensin III, one of the main effector peptides of the brain renin angiotensin system, exerting a tonic stimulatory effect on the control of blood pressure in hypertensive rats. The distribution of APA in human brain has not been yet studied. We first biochemically characterized human brain APA (apparent molecular mass of 165 and 130 kDa) and we showed that the human enzyme exhibited similar enzymatic characteristics to recombinant mouse APA. Both enzymes had similar sensitivity to Ca(2+). Kinetic studies showed that the K(m) (190 mumol/L) of the human enzyme for the synthetic substrate-l-glutamyl-beta-naphthylamide was close from that of the mouse enzyme (256 mumol/L). Moreover, various classes of inhibitors including the specific and selective APA inhibitor, (S)-3-amino-4-mercapto-butyl sulfonic acid, had similar inhibitory potencies toward both enzymes. Using (S)-3-amino-4-mercapto-butyl sulfonic acid, we then specifically measured the activity of APA in 40 microdissected areas of the adult human brain. Significant heterogeneity was found in the activity of APA in the various analyzed regions. The highest activity was measured in the choroids plexus and the pineal gland. High activity was also detected in the dorsomedial medulla oblongata, in the septum, the prefrontal cortex, the olfactory bulb, the nucleus accumbens, and the hypothalamus, especially in the paraventricular and supraoptic nuclei. Immunostaining of human brain sections at the level of the medulla oblongata strengthened these data, showing for the first time a high density of immunoreactive neuronal cell bodies and fibers in the motor hypoglossal nucleus, the dorsal motor nucleus of the vagus, the nucleus of the solitary tract, the Roller nucleus, the ambiguus nucleus, the inferior olivary complex, and in the external cuneate nucleus. APA immunoreactivity was also visualized in vessels and capillaries in the dorsal motor nucleus of the vagus and the inferior olivary complex. The presence of APA in several human brain nuclei sensitive to angiotensins and involved in blood pressure regulation suggests that APA in humans is an integral component of the brain renin angiotensin system and strengthens the idea that APA inhibitors could be clinically tested as an additional therapy for the treatment of certain forms of hypertension.
Published: 2008

41. Jacques Benoit lecture: the neuroendocrine view of the angiotensin and apelin systems

Author: Claude Kordon, Catherine Llorens-Cortes, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Llorens Cortes, Catherine, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), IFR Necker-Enfants Malades ( IRNEM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH : Glutamyl Aminopeptidase, MESH: Signal Transduction, Angiotensin receptor, Vasopressin, Endocrinology, Diabetes and Metabolism, MESH : Models, Biological, MESH: Receptors, G-Protein-Coupled, MESH : Tissue Distribution, 0302 clinical medicine, Endocrinology, MESH: Renin-Angiotensin System, MESH: Animals, Receptor, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Glutamyl Aminopeptidase, 0303 health sciences, MESH : Rats, MESH: Blood Pressure, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Apelin, MESH: Enzyme Inhibitors, MESH : Receptors, G-Protein-Coupled, hormones, hormone substitutes, and hormone antagonists, MESH : Angiotensins, medicine.medical_specialty, MESH: Rats, Neuropeptide, Biology, MESH: Cardiovascular Physiological Phenomena, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Brain, Internal medicine, Renin–angiotensin system, MESH : Blood Pressure, medicine, MESH: Tissue Distribution, MESH: Intercellular Signaling Peptides and Proteins, MESH : Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Apelin receptor, MESH : Signal Transduction, MESH : Enzyme Inhibitors, MESH: Angiotensins, MESH: Humans, MESH : Water-Electrolyte Balance, MESH : Cardiovascular Physiological Phenomena, Endocrine and Autonomic Systems, MESH : Humans, MESH: Models, Biological, MESH : Brain, MESH: Neurosecretory Systems, MESH: Water-Electrolyte Balance, MESH : Animals, MESH : Neurosecretory Systems, MESH : Renin-Angiotensin System, 030217 neurology & neurosurgery, Homeostasis
Abstract: International audience; The hyperactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III display the same affinity for type 1 and type 2 Ang II receptors. Both peptides, injected intracerebroventricularly, similarly increase arginine vasopressin (AVP) release and blood pressure (BP); however, because Ang II is converted in vivo to Ang III, the identity of the true effector is unknown. We review new insights into the predominant role of brain Ang III in the control of BP, underlining the fact that brain aminopeptidase A (APA), the enzyme generating brain Ang III, may therefore be an interesting candidate target for the treatment of hypertension. This justifies the development of potent systemically active APA inhibitors, such as RB150, as prototypes of a new class of antihypertensive agents for the treatment of certain forms of hypertension. We also searched for a putative angiotensin receptor subtype specific for Ang III and isolated a seven transmembrane-domain G protein-coupled receptor corresponding to the receptor for apelin, a newly-discovered peptide isolated from bovine stomach. Apelin and its receptor are expressed in magnocellular vasopressinergic neurones in the hypothalamus. The central injection of apelin in lactating rats decreases the phasic electrical activity of vasopressinergic neurones and the systemic secretion of AVP, inducing water diuresis. Apelin is therefore a natural inhibitor of the antidiuretic effect of AVP. In addition, systemic administration of apelin decreases BP, improves cardiac contractility and reduces cardiac loading. The development of nonpeptide agonists of the apelin receptor may provide new therapeutic tools for treating water retention, hyponatraemia and cardiovascular diseases. Angiotensins and apelin thus exert opposing but complementary effects, and are thereby determinant for the maintenance of body fluid homeostasis and cardiovascular functions.
Published: 2008

42. Functional dissociation between apelin receptor signaling and endocytosis: implications for the effects of apelin on arterial blood pressure

Author: Céline Fassot, Bernard Maigret, Xavier Iturrioz, Said El Messari, Rodrigo Alvear-Perez, Catherine Llorens-Cortes, Nadia De Mota, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), INSERM U691 - Collège de France (INSERM ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Llorens Cortes, Catherine, and Fassot, Céline
Subjects: MESH: Signal Transduction, medicine.medical_specialty, MESH: Rats, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Physiology, Blood Pressure, MESH: Carrier Proteins, MESH: Receptors, G-Protein-Coupled, Endocytosis, Rats, Inbred WKY, Receptors, G-Protein-Coupled, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, MESH: Structure-Activity Relationship, Internal medicine, Internal Medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Medicine, MESH: Animals, MESH: Peptide Fragments, Apelin receptor, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, MESH: Blood Pressure, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Peptide Fragments, Rats, Apelin, Endocrinology, Blood pressure, 030220 oncology & carcinogenesis, MESH: Endocytosis, Intercellular Signaling Peptides and Proteins, Functional dissociation, Carrier Proteins, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, MESH: Rats, Inbred WKY, Signal Transduction
Abstract: International audience; Apelin is a peptide involved in the regulation of body fluid homeostasis and cardiovascular functions, that was recently isolated as the endogenous ligand for the human orphan APJ receptor, a G protein-coupled receptor which shares 31% amino-acid sequence identity with the angiotensin II type 1 receptor. The predominant molecular forms of apelin naturally occuring in vivo are apelin 36, apelin 17 (K17F) and the pyroglutamyl form of apelin 13 (pE13F). We investigated the structure-activity relationships of apelin at the rat apelin receptor, tagged at its C-terminal end with enhanced green fluorescent protein and stably expressed in CHO cells. We compared the abilities of N- and C-terminal deleted fragments of K17F (KFRRQRPRLSHKGPMPF) to bind with high affinity to the apelin receptor, to inhibit cAMP production and to induce apelin receptor internalization. The first five N-terminal and the last two C-terminal amino acids of K17F were not essential for apelin binding or cAMP response. In contrast, deletion of the arginine in position 6 drastically decreased binding and cAMP response. The full-length sequence of K17F was the most potent inducer of apelin receptor internalization because successive N-terminal amino-acid deletions progressively reduced internalization and the removal of a single amino acid, the phenylalanine in position 17 at the C-terminus of K17F abolished this process. Thus, K16P binds with high affinity to the apelin receptor and strongly inhibits cAMP production, but does not induce apelin receptor endocytosis. These data indicate that apelin receptor signaling (coupling to Gi) and endocytosis are functionally dissociated, possibly reflecting the existence of several conformational states of this receptor, stabilized by the binding of different apelin fragments to the receptor. We then investigated the consequences for biological activity of this functional dissociation by evaluating the effects of various apelin fragments, injected iv, on arterial blood pressure in normotensive Wistar Kyoto rats. We showed that apelin fragments, that did not induce receptor internalization in vitro but kept their ability to activate receptor coupling to Gi, did not decrease arterial blood pressure. Our data showed that hypotensive actions of apelin peptides correlate with the ability of those ligands to internalize. Thus, the depressor response of apelin may be controlled by apelin receptor endocytosis, which is probably required for initiation of a second wave of signal transduction. The development of biaised agonists of the apelin receptor capable of promoting only one specific signal transduction pathway may therefore offer new therapeutic avenues for the treatment of cardiovascular disorders.
Published: 2007

43. Cellular localization of apelin and its receptor in the anterior pituitary: evidence for a direct stimulatory action of apelin on ACTH release

Author: Marie-Thérèse Bluet-Pajot, Rodrigo Alvear-Perez, Philippe Zizzari, Catherine Llorens-Cortes, Annabelle Réaux-Le Goazigo, Jacques Epelbaum, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Llorens Cortes, Catherine
Subjects: Male, Pituitary gland, Endocrinology, Diabetes and Metabolism, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, MESH: Base Sequence, MESH : Tissue Distribution, Receptors, G-Protein-Coupled, Rats, Sprague-Dawley, 0302 clinical medicine, MESH: Cricetulus, MESH: Pituitary Gland, MESH: Ligands, MESH : CHO Cells, Tissue Distribution, MESH: Animals, MESH: Peptide Fragments, MESH : Ligands, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Cyclic AMP, MESH: Pituitary Gland, Anterior, MESH : Cricetinae, MESH : Protein Binding, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin, MESH : Adrenocorticotropic Hormone, Intercellular Signaling Peptides and Proteins, MESH : Carrier Proteins, medicine.medical_specialty, endocrine system, MESH : Cell Membrane, MESH : Cricetulus, MESH: Carrier Proteins, Adrenocorticotropic hormone, 03 medical and health sciences, Adrenocorticotropic Hormone, Anterior pituitary, Pituitary Gland, Anterior, MESH: CHO Cells, Physiology (medical), MESH: Protein Binding, MESH: Tissue Distribution, MESH: Adrenocorticotropic Hormone, MESH: Humans, MESH: Molecular Sequence Data, MESH : Humans, Peptide Fragments, Endocrinology, Carrier Proteins, 030217 neurology & neurosurgery, MESH : Molecular Sequence Data, Physiology, MESH: Corticotrophs, MESH: Cricetinae, MESH : Models, Biological, MESH: Rats, Sprague-Dawley, Rats, Inbred WKY, MESH : Pituitary Gland, Receptor, Corticotrophs, Cellular localization, MESH: Cyclic AMP, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Apelin Receptors, MESH : Rats, MESH : Forskolin, medicine.anatomical_structure, MESH: Pituitary Hormones, Anterior, MESH: Calcium, MESH : Receptors, G-Protein-Coupled, MESH : Transfection, MESH: Forskolin, hormones, hormone substitutes, and hormone antagonists, MESH: Rats, Inbred WKY, Endocrine gland, MESH: Rats, MESH : Male, MESH : Rats, Inbred WKY, Biology, Models, Biological, MESH : Pituitary Hormones, Anterior, MESH : Pituitary Gland, Anterior, Pituitary Hormones, Anterior, Internal medicine, medicine, Animals, MESH : Calcium, 030304 developmental biology, Apelin receptor, MESH: Transfection, MESH : Peptide Fragments, MESH: Models, Biological, MESH : Corticotrophs, MESH : Rats, Sprague-Dawley, MESH: Male, Rats, MESH : Peptide Hormones, MESH: Peptide Hormones, MESH : Base Sequence, MESH : Animals, MESH: Cell Membrane
Abstract: Apelin is a bioactive peptide recently identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. The presence of apelin-immunoreactive nerve fibers, together with the detection of apelin receptor mRNA in the parvocellular part of the paraventricular nucleus and the stimulatory action of apelin on corticotropin-releasing hormone release, indicate that apelin modulates adrenocorticotropin (ACTH) release via an indirect action on the hypothalamus. However, a direct action of apelin in the anterior pituitary cannot be excluded. Here, we provided evidence for the existence of an apelinergic system within the adult male rat pituitary gland. Double immunofluorescence staining indicated that apelin is highly coexpressed in the anterior pituitary, mainly in corticotrophs (96.5 ± 0.3%) and to a much lower extent in somatotropes (3.2 ± 0.2%). Using in situ hybridization combined with immunohistochemistry, a high expression of apelin receptor mRNA was also found in corticotrophs, suggesting a local interaction between apelin and ACTH. In an ex vivo perifusion system of anterior pituitaries, apelin 17 (K17F, 10−6M) significantly increased basal ACTH release by 41%, whereas apelin 10 (R10F, 10−6M), an inactive apelin fragment, was ineffective. In addition, K17F but not R10F induced a dose-dependent increase in K+-evoked ACTH release, with maximal increase being observed for a 10−6M concentration. Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions.
Published: 2007

44. Hypoxia-sensing properties of the newborn rat ventral medullary surface in vitro

Author: Voituron, Nicolas, Frugière, Alain, Saadani-Makki, Fadoua, Champagnat, Jean, Bodineau, Laurence, Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques, Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pediatric Critical Care Department, Children's Hospital of Michigan, Children's Hospital of Michigan, Neurobiologie génétique et intégrative (NGI), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques - EA UPJV 3901 (EA3901), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Medulla Oblongata, In Vitro Techniques, Synaptic Transmission, Feedback, Rats, Oxygen, Rats, Sprague-Dawley, Animals, Newborn, Biological Clocks, Respiratory Mechanics, Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hypoxia, Proto-Oncogene Proteins c-fos, Neuroscience
Abstract: The ventral medullary surface (VMS) is a region known to exert a respiratory stimulant effect during hypercapnia. Several studies have suggested its involvement in the central inhibition of respiratory rhythm caused by hypoxia. We studied brainstem-spinal cord preparations isolated from newborn rats transiently superfused with a very low O(2) medium, causing reversible respiratory depression, to characterize the participation of the VMS in hypoxic respiratory adaptation. In the presence of 0.8 mm Ca(2+), very low O(2) medium induced an increase in c-fos expression throughout the VMS. The reduction of synaptic transmission and blockade of the respiratory drive by 0.2 mm Ca(2+)-1.6 mm Mg(2+) abolished c-fos expression in the medial VMS (at the lateral edge of the pyramidal tract) but not in the perifacial retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) VMS, suggesting the existence of perifacial RTN/pFRG hypoxia-sensing neurons. In the presence of Ca(2+) (0.8 mm), lesioning experiments suggested a physiological difference in perifacial RTN/pFRG VMS between the lateral VMS (beneath the ventrolateral part of the facial nucleus) and the middle VMS (beneath the ventromedial part of the facial nucleus), at least in newborn rats. The lateral VMS lesion, corresponding principally to the most rostral part of the pFRG, produced hypoxia-induced stimulation, whereas the middle VMS lesion, corresponding to the main part of the RTN, abolished hypoxic excitation. This may involve relay via the medial VMS, which is thought to be the parapyramidal group.
Published: 2006

45. Effect of postnatal exposure to caffeine on the pattern of adenosine A1 receptor distribution in respiration-related nuclei of the rat brainstem

Author: Rosario Pásaro, A. Frugière, F. Saadani-Makki, L. Bodineau, Susana P. Gaytán, Nicole Larnicol, Pediatric Critical Care Department, Children's Hospital of Michigan, Children's Hospital of Michigan, Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques - EA UPJV 3901 (EA3901), Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, MESH: Rats, Sprague-Dawley, MESH: Animals, Newborn, MESH: Caffeine, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH: Gene Expression Regulation, Developmental, MESH: Animals, 0303 health sciences, Respiration, Age Factors, Gene Expression Regulation, Developmental, 3. Good health, medicine.anatomical_structure, Female, Brainstem, Caffeine, medicine.drug, medicine.medical_specialty, MESH: Rats, Central nervous system, Adenosinergic, Biology, MESH: Receptor, Adenosine A1, MESH: Central Nervous System Stimulants, 03 medical and health sciences, Cellular and Molecular Neuroscience, Adenosine A1 receptor, Internal medicine, medicine, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, MESH: Age Factors, MESH: Respiration, Receptor, Adenosine A1, Endocrine and Autonomic Systems, Adenosine, Pons, MESH: Male, Rats, Autonomic nervous system, Endocrinology, Animals, Newborn, chemistry, MESH: Brain Stem, Central Nervous System Stimulants, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery, Brain Stem
Abstract: Caffeine, which belongs to the methylxantine family of compounds, is commonly ingested in a range of beverages such as coffee, tea, and cola drinks. It is also used therapeutically and is frequently employed in the treatment of respiratory disturbances in human neonates. The aim of the present work has been to examine the ontogeny of the adenosine A1 receptor system in the brainstem of the newborn rat following postnatal treatment with caffeine to mimic the therapeutic administration of caffeine to premature human infants. The effect of this postnatal exposure to caffeine on the gradual appearance of adenosine A1 receptors was analysed by determining immunohistochemically the distribution of the receptors. The main difference between control animals and animals exposed to caffeine was the transient increase (only at postnatal day 6) in the number of immunopositive neurons in two brainstem areas, the ventrolateral medulla and the rostral dorsolateral pons, in caffeine-treated rat pups, or more specifically, the parabrachial and Kölliker-Fuse nuclei, both of which are classically associated with respiratory control. With previous research highlighting the important role played by the rostral pons in respiratory modulation by the adenosine A1 receptor system, it is thus possible that postnatal exposure to caffeine modulates the ontogeny of the adenosine A1 receptor network. This could imply that the role of caffeine to decrease the incidence of neonatal respiratory disturbances may be due to the earlier than normal development of the adenosinergic system in the brain.
Published: 2006

46. Organic contaminant loads into the Western Mediterranean Sea: Estimate of Ebro River inputs

Author: Gómez-Gutiérrez, A.I, Jover, Emmanuel, Bodineau, Laurence, Albaiges, J., Bayona, J.M, Avelin, Herve, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques, Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dysrégulations Métaboliques Acquises et Génétiques. Approches moléculaires, physiologiques et neurobiologiques - EA UPJV 3901 (EA3901), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Dysrégulations Métaboliques Acquises et Génétiques (UPRES EA 3901), and Université de Picardie Jules Verne (UPJV)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2006

47. Tyrosine kinase and mitogen-activated protein kinase/extracellularly regulated kinase differentially regulate intracellular calcium concentration responses to angiotensin II/III and bradykinin in rat cortical thick ascending limb

Author: Annette Hus-Citharel, Catherine Llorens-Cortes, Jeannine Marchetti, Pierre Corvol, Xavier Iturrioz, Llorens Cortes, Catherine, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie et pathologie expérimentale vasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iturrioz, Xavier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MAPK/ERK pathway, Male, [SDV]Life Sciences [q-bio], Angiotensin III, MESH: Rats, Sprague-Dawley, Calcium in biology, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, [CHIM] Chemical Sciences, MESH: Animals, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, Cerebral Cortex, Mitogen-Activated Protein Kinase 1, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Kinetics, Angiotensin II, Protein-Tyrosine Kinases, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV] Life Sciences [q-bio], MESH: Enzyme Inhibitors, MESH: Calcium, MESH: Angiotensin II, Tyrosine kinase, hormones, hormone substitutes, and hormone antagonists, Proto-oncogene tyrosine-protein kinase Src, MESH: Mitogen-Activated Protein Kinase 1, medicine.medical_specialty, Bisindolylmaleimide, MESH: Rats, Biology, Bradykinin, MESH: Protein-Tyrosine Kinases, 03 medical and health sciences, Internal medicine, medicine, [CHIM]Chemical Sciences, Animals, Protein kinase C, 030304 developmental biology, Flavonoids, MESH: Bradykinin, MESH: Male, MESH: Cerebral Cortex, Rats, Kinetics, chemistry, Calcium, MESH: Flavonoids, 030217 neurology & neurosurgery
Abstract: International audience; The cortical thick ascending limb (CTAL) coexpresses angiotensin (Ang) II/Ang III receptor type 1A (AT(1A)-R) and bradykinin (BK) receptor type 2 (B2-R). In several cell types, these two receptors share the same signaling pathways, although their physiological functions are often opposite. In CTAL, little is known about the intracellular transduction events leading to the final physiological response induced by these two peptides. We investigated and compared in this segment the action of Ang II/III and BK on intracellular calcium concentration ([Ca2+]i) response and metabolic CO2 production, an index of Na+ transport, by using inhibitors of protein kinase C (bisindolylmaleimide), Src tyrosine kinase (herbimycin A and PP2), and MAPK/ERK (PD98059 and UO126). Ang II/III and BK (10(-7) mol/liter) released Ca2+ from the same intracellular pools but activated different Ca2+ entry pathways. Ang II/III- or BK-induced [Ca2+]i increases were similarly potentiated by bisindolylmaleimide. Herbimycin A and PP2 decreased similarly the [Ca2+]i responses induced by Ang II/III and BK. In contrast, PD98059 and UO126 affected the effects of BK to a larger extent than those of Ang II/III. Especially, the Ca2+ influx induced by BK was more strongly inhibited than that induced by Ang II/III in the presence of both compounds. The Na+ transport was inhibited by BK and stimulated by Ang II/III. The inhibitory action of BK on Na+ transport was blocked by UO126, whereas the stimulatory response of Ang II/III was potentiated by UO126 but blocked by bisindolylmaleimide. These data suggest that the inhibitory effect of BK on Na+ transport seems to be directly mediated by an increase in Ca2+ influx dependent on MAPK/ERK pathway activation. In contrast, the stimulatory effect of Ang II/III on Na+ transport is more complex and involves PKC and MAPK/ERK pathways.
Published: 2006

48. Roles of brain angiotensins II and III in thirst and sodium appetite

Author: Wendy L. Wilson, Catherine Llorens-Cortes, John W. Wright, Robert C. Speth, Joseph W. Harding, Bernard P. Roques, Department of Psychology, University of Washington [Seattle], Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology, and Research Institute in Pharmaceutical Sciences, The University of Mississippi [Oxford], Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University (WSU), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Llorens Cortes, Catherine, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Washington State University ( WSU ), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Captopril, Angiotensin III, Appetite, MESH : Dose-Response Relationship, Drug, Angiotensin-Converting Enzyme Inhibitors, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Thirst, MESH: Dose-Response Relationship, Drug, Rats, Sprague-Dawley, MESH: Furosemide, 0302 clinical medicine, Methionine, Sodium Potassium Chloride Symporter Inhibitors, Furosemide, MESH: Animals, MESH : Thirst, media_common, computer.programming_language, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Chemistry, sed, MESH : Rats, General Neuroscience, Angiotensin II, MESH : Sodium Chloride, Dietary, MESH: Angiotensin-Converting Enzyme Inhibitors, Brain, MESH : Injections, Intraventricular, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Furosemide, MESH : Angiotensin-Converting Enzyme Inhibitors, MESH: Angiotensin II, medicine.symptom, MESH: Injections, Intraventricular, hormones, hormone substitutes, and hormone antagonists, medicine.drug, MESH : Appetite, medicine.medical_specialty, MESH: Rats, media_common.quotation_subject, Sodium, MESH : Male, MESH : Sulfonic Acids, MESH : Captopril, chemistry.chemical_element, MESH : Angiotensin II, 03 medical and health sciences, MESH: Brain, Internal medicine, MESH : Angiotensin III, Renin–angiotensin system, medicine, Animals, Sodium Chloride, Dietary, MESH: Sodium Chloride, Dietary, Molecular Biology, Injections, Intraventricular, MESH : Methionine, Dose-Response Relationship, Drug, MESH: Captopril, MESH : Rats, Sprague-Dawley, MESH: Male, Rats, Endocrinology, MESH : Brain, MESH: Methionine, MESH : Sodium Potassium Chloride Symporter Inhibitors, MESH: Sulfonic Acids, MESH: Thirst, MESH: Appetite, Neurology (clinical), MESH : Animals, MESH: Sodium Potassium Chloride Symporter Inhibitors, Sulfonic Acids, computer, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; The current study examined the effects of intracerebroventricular (icv) infused aminopeptidase-resistant analogs of angiotensin II (AngII) and angiotensin III (AngIII) on thirst and sodium appetite. The analogs, [D-Asp1D-Arg2]AngII and [D-Arg1]AngIII, were further protected from degradation by pretreatment with the aminopeptidase A inhibitor, EC33, or the aminopeptidase N inhibitor, PC18. Prior to icv infusions, rats were sodium depleted with furosemide, followed by the angiotensin-converting enzyme inhibitor captopril, to block endogenous angiotensin formation. Both angiotensin analogs, at either of the two doses, were capable of eliciting fluid intakes of water and 0.3 M NaCl. Water and saline intakes were increased to a similar extent by 125 and 1250 pmol of [D-Asp1D-Arg2]AngII. [D-Arg1]AngIII produced a dose-dependent increase in water intake, whereas saline intake was equivalently increased by the 125 and 1250 pmol infusions. Pretreatment with EC33 or PC18 decreased water and saline intakes in response to [D-Asp1D-Arg2]AngII, while pretreatment with PC18 altered the time course of the [D-Arg1]AngIII-induced water and saline intakes. The ability of both inhibitors to decrease, but not completely block, AngII analog-induced intakes, coupled with the altered time course of the responses induced by the AngIII analog in the presence of PC18, supports the hypothesis that both AngII and AngIII are active ligands in brain angiotensin-mediated thirst and sodium appetite. However, these results do not resolve the primary question of whether conversion of AngII to AngIII is a prerequisite to dipsogenic and salt appetite responses in the brain.
Published: 2005

49. L'apéline, un inhibiteur naturel de l'effet antidiurétique de la vasopressine

Author: Llorens-Cortès, Catherine, Beaudet, Alain, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Ces travaux ont été financés par l'Inserm, le CNRS, le Fonds de la Recherche en Santé du Québec, les Instituts de recherche en santé du Canada, le programme de coopération France-Hongrie BALATON et la Société Française d'Hypertension., Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Maylin, Françoise
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Molecular Sequence Data, MESH: Conserved Sequence, MESH: Humans, MESH: Sequence Alignment, MESH: Carrier Proteins, MESH: Amino Acid Sequence, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Neuropeptides, MESH: Research Support, Non-U.S. Gov't, MESH: Body Fluids, MESH: Brain, nervous system, MESH: Homeostasis, MESH: Sequence Homology, Amino, MESH: Ligands, MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: English Abstract, hormones, hormone substitutes, and hormone antagonists
Abstract: Apelin is a peptide that was recently isolated as the endogenous ligand for the human orphan APJ receptor, a G protein-coupled receptor which shares 31 % amino-acid sequence identity with the angiotensin type 1 receptor. Apelin naturally occurs in the brain and plasma as 13 (pE13F) and 17 amino-acid (K17F) fragments of a single pro-peptide precursor. In transfected CHO cells, K17F and pE13F bind with high affinity to the rat APJ receptor, promote receptor internalization, and inhibit forskolin-induced cAMP formation. In the same cells, pE13F activates MAP kinase and PI3 kinase pathways. Apelin and APJ receptors are both widely distributed in the brain but are particularly highly expressed in the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. Dual labeling studies demonstrate that within these two nuclei, apelin and its receptor are colocalized with vasopressin (AVP) in a subset of magnocellular neurons. In lactating rats, characterized by increases in both synthesis and release of AVP, central injection of apelin inhibits the phasic electrical activity of AVP neurons, reduces plasma AVP levels, and increases aqueous diuresis. Moreover, water deprivation, while increasing the activity of AVP neurons, reduces plasma apelin concentrations and induces an intra-neuronal pile up of the peptide, thereby decreasing the inhibitory effect of apelin on AVP release and preventing additional water loss at the kidney level. Taken together, these data demonstrate that apelin counteracts the effects of AVP in the maintenance of body fluid homeostasis. In addition, apelin and its receptor are present in the cardiovascular system, i.e. heart, kidney and vessels. Systemically administered apelin reduces arterial blood pressure, increases cardiac contractility and reduces cardiac loading. The development of non peptidic analogs of apelin may therefore offer new therapeutic avenues for the treatment of cardiovascular disorders.
Published: 2005

50. Role of angiotensin III in hypertension

Author: Xavier Iturrioz, Catherine Llorens-Cortes, Bernard P. Roques, Annabelle Réaux-Le Goazigo, Cédric Claperon, Céline Fassot, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Iturrioz, Xavier, Fassot, Céline, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Pharmacologie Chimique et Génétique ( UPCG - UMR_S 640/UMR 8151 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 )
Subjects: Nephrology, MESH : Glutamyl Aminopeptidase, [SDV]Life Sciences [q-bio], Angiotensin III, Blood Pressure, Pharmacology, MESH : Antihypertensive Agents, MESH: Hypertension, 0302 clinical medicine, [CHIM] Chemical Sciences, MESH: Animals, Receptor, MESH: Glutamyl Aminopeptidase, 0303 health sciences, Effector, Brain, MESH : Hypertension, MESH: Blood Pressure, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Angiotensin III, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], Hypertension, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, Glutamyl Aminopeptidase, 03 medical and health sciences, MESH: Brain, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Internal medicine, MESH : Angiotensin III, Renin–angiotensin system, Internal Medicine, medicine, MESH : Blood Pressure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [CHIM]Chemical Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Antihypertensive Agents, 030304 developmental biology, MESH: Antihypertensive Agents, MESH: Humans, business.industry, MESH : Humans, Blood pressure, Endocrinology, MESH : Brain, Glutamyl aminopeptidase, MESH : Animals, business, 030217 neurology & neurosurgery
Abstract: International audience; The hyperactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. Among the main bio-active peptides of the brain RAS, angiotensin (Ang) II and Ang III display the same affinity for type 1 and type 2 Ang II receptors. Both peptides, injected intracerebroventricularly, similarly increase blood pressure (BP); however, because Ang II is converted in vivo to Ang III, the identity of the true effector is unknown. In this article, we review new insights into the predominant role of brain Ang III in the control of BP, underlining the fact that brain aminopeptidase A (APA), the enzyme-forming central Ang III, could constitute a putative central therapeutic target for the treatment of hypertension. This justifies the development of potent systemically active APA inhibitors, such as RB150, as prototypes of a new class of antihypertensive agents for the treatment of certain forms of hypertension.
Published: 2005

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