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10 results on '"Severine Denoyelle"'

1. Growth hormone secretagogues modulate inflammation and fibrosis in mdx mouse model of Duchenne muscular dystrophy

Author

Brigida Boccanegra, Ornella Cappellari, Paola Mantuano, Daniela Trisciuzzi, Antonietta Mele, Lisamaura Tulimiero, Michela De Bellis, Santa Cirmi, Francesca Sanarica, Alessandro Giovanni Cerchiara, Elena Conte, Ramona Meanti, Laura Rizzi, Elena Bresciani, Severine Denoyelle, Jean-Alain Fehrentz, Gabriele Cruciani, Orazio Nicolotti, Antonella Liantonio, Antonio Torsello, and Annamaria De Luca

Subjects
Duchenne muscular dystrophy, mdx mouse, growth hormone secretagogues, skeletal muscle, fibrosis, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionGrowth hormone secretagogues (GHSs) exert multiple actions, being able to activate GHS-receptor 1a, control inflammation and metabolism, to enhance GH/insulin-like growth factor-1 (IGF-1)-mediated myogenesis, and to inhibit angiotensin-converting enzyme. These mechanisms are of interest for potentially targeting multiple steps of pathogenic cascade in Duchenne muscular dystrophy (DMD).MethodsHere, we aimed to provide preclinical evidence for potential benefits of GHSs in DMD, via a multidisciplinary in vivo and ex vivo comparison in mdx mice, of two ad hoc synthesized compounds (EP80317 and JMV2894), with a wide but different profile. 4-week-old mdx mice were treated for 8 weeks with EP80317 or JMV2894 (320 µg/kg/d, s.c.).ResultsIn vivo, both GHSs increased mice forelimb force (recovery score, RS towards WT: 20% for EP80317 and 32% for JMV2894 at week 8). In parallel, GHSs also reduced diaphragm (DIA) and gastrocnemius (GC) ultrasound echodensity, a fibrosis-related parameter (RS: ranging between 26% and 75%). Ex vivo, both drugs ameliorated DIA isometric force and calcium-related indices (e.g., RS: 40% for tetanic force). Histological analysis highlighted a relevant reduction of fibrosis in GC and DIA muscles of treated mice, paralleled by a decrease in gene expression of TGF-β1 and Col1a1. Also, decreased levels of pro-inflammatory genes (IL-6, CD68), accompanied by an increment in Sirt-1, PGC-1α and MEF2c expression, were observed in response to treatments, suggesting an overall improvement of myofiber metabolism. No detectable transcript levels of GHS receptor-1a, nor an increase of circulating IGF-1 were found, suggesting the presence of a novel receptor-independent mechanism in skeletal muscle. Preliminary docking studies revealed a potential binding capability of JMV2894 on metalloproteases involved in extracellular matrix remodeling and cytokine production, such as ADAMTS-5 and MMP-9, overactivated in DMD.DiscussionOur results support the interest of GHSs as modulators of pathology progression in mdx mice, disclosing a direct anti-fibrotic action that may prove beneficial to contrast pathological remodeling.

Published
2023
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2. Concerted conformational dynamics and water movements in the ghrelin G protein-coupled receptor

Author

Maxime Louet, Marina Casiraghi, Marjorie Damian, Mauricio GS Costa, Pedro Renault, Antoniel AS Gomes, Paulo R Batista, Céline M'Kadmi, Sophie Mary, Sonia Cantel, Severine Denoyelle, Khoubaib Ben Haj Salah, David Perahia, Paulo M Bisch, Jean-Alain Fehrentz, Laurent J Catoire, Nicolas Floquet, and Jean-Louis Banères

Subjects
GPCR, hydration, signaling, Medicine, Science, Biology (General), QH301-705.5
Abstract

There is increasing support for water molecules playing a role in signal propagation through G protein-coupled receptors (GPCRs). However, exploration of the hydration features of GPCRs is still in its infancy. Here, we combined site-specific labeling with unnatural amino acids to molecular dynamics to delineate how local hydration of the ghrelin receptor growth hormone secretagogue receptor (GHSR) is rearranged upon activation. We found that GHSR is characterized by a specific hydration pattern that is selectively remodeled by pharmacologically distinct ligands and by the lipid environment. This process is directly related to the concerted movements of the transmembrane domains of the receptor. These results demonstrate that the conformational dynamics of GHSR are tightly coupled to the movements of internal water molecules, further enhancing our understanding of the molecular bases of GPCR-mediated signaling.

Published
2021
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3. LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

Author

Emilio R. Mustafá, Santiago Cordisco González, Marjorie Damian, Sonia Cantel, Severine Denoyelle, Renaud Wagner, Helgi B. Schiöth, Jean-Alain Fehrentz, Jean-Louis Banères, Mario Perelló, and Jesica Raingo

Subjects
GPCR, heterodimerization, Cav2.2, ghrelin receptor, dopamine receptor, constitutive activity, Therapeutics. Pharmacology, RM1-950
Abstract

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.

Published
2021
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4. GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner

Author

Gimena Fernandez, Agustina Cabral, Pablo N. De Francesco, Maia Uriarte, Mirta Reynaldo, Daniel Castrogiovanni, Guillermina Zubiría, Andrés Giovambattista, Sonia Cantel, Severine Denoyelle, Jean-Alain Fehrentz, Virginie Tolle, Helgi B. Schiöth, and Mario Perello

Subjects
Pharmacology, Male, Neurons, Hypothalamo-Hypophyseal System, Corticotropin-Releasing Hormone, Pituitary-Adrenal System, Cell Biology, Ghrelin, Cellular and Molecular Neuroscience, Eating, Mice, Molecular Medicine, Animals, Food Deprivation, Receptors, Ghrelin, Molecular Biology, Antimicrobial Cationic Peptides, Paraventricular Hypothalamic Nucleus
Abstract

Prolonged fasting is a major challenge for living organisms. An appropriate metabolic response to food deprivation requires the activation of the corticotropin-releasing factor-producing neurons of the hypothalamic paraventricular nucleus (PVHWe estimated the activation of the PVHWe found that food deprivation results in the activation of the PVHFood deprivation-induced activation of the PVH

Published
2022

5. Concerted conformational dynamics and water movements in the ghrelin G protein-coupled receptor

Author

Laurent J. Catoire, Sonia Cantel, Marjorie Damian, Jean-Alain Fehrentz, Maxime Louet, Antoniel As Gomes, Jean-Louis Banères, Sophie Mary, Paulo R. Batista, David Perahia, Paulo Mascarello Bisch, Mauricio Gs Costa, Khoubaib Ben Haj Salah, Céline M'Kadmi, Marina Casiraghi, Pedro Renault, Severine Denoyelle, Nicolas Floquet, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie physico-chimique des protéines membranaires (LBPC-PM (UMR_7099)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Department of Molecular and Cellular Physiology [Stanford], Stanford Medicine, Stanford University-Stanford University, Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Universidade Federal do Rio de Janeiro (UFRJ), This work was supported by CNRS, Université de Montpellier, Agence Nationale de la Recherche (ANR-17-CE11-0011, ANR-17-CE11-22, ANR-17-CE18-0022), EpiGenMed Labex (post-doctoral fellowship to KBH) and DYNAMO Labex (post-doctoral fellowship to MC). This programreceived funding from the European Union’s Horizon 2020 research and innovation programmeunder the Marie Sklodowska-Curie grant agreement n˚ 799376. Mass spectrometry analyses wereperformed on the instruments located in the IBMM platform of instrumentation, Laboratoire deMesures Physiques (LMP) of Université de Montpellier. We thank GENCI (Grand EquipementNational de Calcul Intensif), CINES (Centre Informatique National de l’Enseignement Supérieur), and IDRIS (Institut du développement et des ressources en informatique scientifique) for computational, ANR-17-CE11-0011,allosig,allostérie, dynamique conformationnelle et signalisation via les RCPG(2017), ANR-17-CE11-0022,GPCteR,Mécanismes moléculaires des régions C-terminales désordonnées et fonctionnelles des RCPG et impact sur les voies de la signalisation cellulaire dépendantes de l'arrestine(2017), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)

Subjects
QH301-705.5, Science, Growth hormone secretagogue receptor, Chemical biology, chemical biology, 010402 general chemistry, Ligands, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, Receptors, G-Protein-Coupled, 03 medical and health sciences, Molecular dynamics, GPCR, Biochemistry and Chemical Biology, biochemistry, Humans, Biology (General), Receptor, Receptors, Ghrelin, 030304 developmental biology, G protein-coupled receptor, chemistry.chemical_classification, 0303 health sciences, General Immunology and Microbiology, [SDV.BA]Life Sciences [q-bio]/Animal biology, General Neuroscience, digestive, oral, and skin physiology, E. coli, General Medicine, Ghrelin, 0104 chemical sciences, Amino acid, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Transmembrane domain, chemistry, Biophysics, Medicine, signaling, hydration, Research Article, Human, Signal Transduction
Abstract

International audience; There is increasing support for water molecules playing a role in signal propagation through G protein-coupled receptors (GPCRs). However, exploration of the hydration features of GPCRs is still in its infancy. Here, we combined site-specific labeling with unnatural amino acids to molecular dynamics to delineate how local hydration of the ghrelin receptor growth hormone secretagogue receptor (GHSR) is rearranged upon activation. We found that GHSR is characterized by a specific hydration pattern that is selectively remodeled by pharmacologically distinct ligands and by the lipid environment. This process is directly related to the concerted movements of the transmembrane domains of the receptor. These results demonstrate that the conformational dynamics of GHSR are tightly coupled to the movements of internal water molecules, further enhancing our understanding of the molecular bases of GPCR-mediated signaling.

Published
2021

6. Author response: Concerted conformational dynamics and water movements in the ghrelin G protein-coupled receptor

Author

Céline M'Kadmi, Maxime Louet, Paulo R. Batista, Paulo Mascarello Bisch, Sophie Mary, Nicolas Floquet, Marina Casiraghi, Jean-Alain Fehrentz, Khoubaib Ben Haj Salah, Laurent J. Catoire, Sonia Cantel, Jean-Louis Banères, Antoniel As Gomes, David Perahia, Mauricio Gs Costa, Marjorie Damian, Pedro Renault, and Severine Denoyelle

Subjects
Chemistry, Water Movements, Dynamics (mechanics), Biophysics, Ghrelin, G protein-coupled receptor
Published
2021

7. Development of non-peptidic inverse agonists of the ghrelin receptor (GHSR) based on the 1,2,4-triazole scaffold

Author

Sonia Cantel, Jean-Alain Fehrentz, Severine Denoyelle, Catherine Oiry, Gimena Fernandez, Mario Perello, Sylvie Peraldi-Roux, Jean-Louis Banères, Céline M'Kadmi, Guadalupe García Romero, Jacky Marie, Sophie Mary, Mathieu Maingot, Marjorie Damian, Anne-Laure Blayo, Jérémie Neasta, Khoubaib Ben Haj Salah, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Instituto Multidisciplinario de Biología Celular [La Plata] (IMBICE), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Comisión de Investigaciones Científicas [Buenos Aires] (CIC)-Universidad Nacional de la Plata [Argentine] (UNLP), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_specialty, Scaffold, Drug Inverse Agonism, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Carbohydrate metabolism, Ligands, Growth hormone, 01 natural sciences, Islets of Langerhans, 03 medical and health sciences, chemistry.chemical_compound, GTP-Binding Proteins, Internal medicine, Insulin Secretion, Drug Discovery, medicine, Animals, Humans, Inverse agonist, [CHIM]Chemical Sciences, Receptors, Ghrelin, Receptor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 010405 organic chemistry, digestive, oral, and skin physiology, 1,2,4-Triazole, Triazoles, Ligand (biochemistry), Rats, 0104 chemical sciences, HEK293 Cells, Endocrinology, chemistry, Molecular Medicine, Ghrelin
Abstract

International audience; GHSR controls, among others, growth hormone and insulin secretion, adiposity, feeding and glucose metabolism. Therefore, an inverse agonist ligand capable of selectively targeting GHSR and reducing its high constitutive activity appears to be a good candidate for the treatment of obesity-related metabolic diseases. In this context, we present a study that led to the development of several highly potent and selective inverse agonists of GHSR based on the 1,2,4-triazole scaffold. We demonstrate that, depending on the nature of the substituents on positions 3, 4 and 5, 2 this scaffold leads to ligands that exert an intrinsic inverse agonist activity on GHSR-catalyzed G protein activation through the stabilization of a specific inactive receptor conformation. Thanks to an in vivo evaluation, we also show that one of the most promising ligands not only exerts an effect on insulin secretion in rat pancreatic islets but also affects the orexigenic effects of ghrelin in mice.

Published
2020

9. Allosteric modulation of ghrelin receptor signaling by lipids

Author

Marjorie Damian, Maxime Louet, Antoniel Augusto Severo Gomes, Céline M’Kadmi, Séverine Denoyelle, Sonia Cantel, Sophie Mary, Paulo M. Bisch, Jean-Alain Fehrentz, Laurent J. Catoire, Nicolas Floquet, and Jean-Louis Banères

Subjects
Science
Abstract

The membrane is an integral component of the G protein-coupled receptor signaling machinery. Here authors demonstrate that lipids regulate the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific interactions and bulk effects and observe PIP2 and GM3 induced shifts of the conformational equilibrium of GHSR away from its inactive state.

Published
2021
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10. The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist

Author

Jean Martinez, Luc Demange, Luc Brunel, Severine Denoyelle, Johanne Ryan, Damien Boeglin, Céline M'Kadmi, Jean-Alain Fehrentz, Aline Moulin, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Laboratoire des Amino-acides Peptides et Protéines (LAPP), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
medicine.medical_specialty, Peptidomimetic, Clinical Biochemistry, Glycine, Pharmacology, Ligands, Biochemistry, Partial agonist, 03 medical and health sciences, 0302 clinical medicine, In vivo, Internal medicine, medicine, Inverse agonist, Animals, Humans, Receptor, Receptors, Ghrelin, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Molecular Structure, Chemistry, Organic Chemistry, Antagonist, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Triazoles, 3. Good health, Endocrinology, Drug Design, Ghrelin, Secretagogue, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery
Abstract

Ghrelin is a 28-residue peptide acylated with an n-octanoyl group on the Ser 3 residue, predominantly produced by the stomach. Ghrelin displays strong growth hormone (GH) releasing activity, which is mediated by the activation of the so-called GH secretagogue receptor type 1a (GHS-R1a). Given the wide spectrum of biological activities of Ghrelin in neuroendocrine and metabolic pathways, many research groups, including our group, developed synthetic peptide, and nonpeptide GHS-R1a ligands, acting as agonists, partial agonists, antagonists, or inverse agonists. In this highlight article, we will focus on the discovery of a GHS-R1a antagonist compound, JMV 2959, which has been extensively studied in different in vitro and in vivo models. We will first describe the peptidomimetic approach that led us to discover this compound. Then we will review the results obtained with this compound in different studies in the fields of food intake and obesity, addictive behaviors, hyperactivity and retinopathy.

Published
2012

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