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844 results on '"Kostenis, Evi"'

3. A molecular mechanism to diversify Ca2+ signaling downstream of Gs protein-coupled receptors

Author

Brands, Julian, Bravo, Sergi, Jürgenliemke, Lars, Grätz, Lukas, Schihada, Hannes, Frechen, Fabian, Alenfelder, Judith, Pfeil, Cy, Ohse, Paul Georg, Hiratsuka, Suzune, Kawakami, Kouki, Schmacke, Luna C., Heycke, Nina, Inoue, Asuka, König, Gabriele, Pfeifer, Alexander, Wachten, Dagmar, Schulte, Gunnar, Steinmetzer, Torsten, Watts, Val J., Gomeza, Jesús, Simon, Katharina, and Kostenis, Evi

Published
2024
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8. Oxytocin-Modulated Ion Channel Ensemble Controls Depolarization, Integration and Burst Firing in CA2 Pyramidal Neurons

Author

Liu, Jing-Jing, Eyring, Katherine W, König, Gabriele M, Kostenis, Evi, and Tsien, Richard W

Subjects
Biomedical and Clinical Sciences, Medical Physiology, Neurosciences, Mental Health, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Mental health, Neurological, Male, Female, Mice, Animals, Oxytocin, Tetrodotoxin, Receptors, Oxytocin, Pyramidal Cells, Potassium Channels, Inwardly Rectifying, Potassium, CA2, hippocampus, ion channel, neuromodulator, oxytocin, sodium channel, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mechanisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity. Activation of OXTRs inhibits an outward potassium current mediated by inward rectifier potassium channels (I Kir) and thus favoring membrane depolarization. Concomitantly, OXT signaling also diminishes inward current mediated by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels (I h), providing a hyperpolarizing drive. The combined reduction in both I Kir and I h synergistically elevate the membrane resistance and favor dendritic integration while the membrane potential is restrained from quickly depolarizing from rest. As a result, the responsiveness of CA2 PYRs to synaptic inputs is highly sharpened during OXTR activation. Unexpectedly, OXTR signaling also strongly enhances a tetrodotoxin-resistant (TTX-R), voltage-gated sodium current that helps drive the membrane potential to spike threshold and thus promote rhythmic firing. This novel array of OXTR-stimulated ionic mechanisms operates in close coordination and underpins OXT-induced burst firing, a key step in CA2 PYRs' contribution to hippocampal information processing and broader influence on brain circuitry. Our study deepens our understanding of underpinnings of OXT-promoted social memory and general neuropeptidergic control of cognitive states.SIGNIFICANCE STATEMENT Oxytocin (OXT) plays key roles in reproduction, parenting and social and emotional behavior, and deficiency in OXT receptor (OXTR) signaling may contribute to neuropsychiatric disorders. We identified a novel array of OXTR-modulated ion channels that operate in close coordination to retune hippocampal CA2 pyramidal neurons, enhancing responsiveness to synaptic inputs and sculpting output. OXTR signaling inhibits both potassium conductance (I Kir) and mixed cation conductance (I h), engaging opposing influences on membrane potential, stabilizing it while synergistically elevating membrane resistance and electrotonic spread. OXT signaling also facilitates a tetrodotoxin-resistant (TTX-R) Na+ current, not previously described in hippocampus (HP), engaged on further depolarization. This TTX-R current lowers the spike threshold and supports rhythmic depolarization and burst firing, a potent driver of downstream circuitry.

Published
2022

14. A human obesity-associated MC4R mutation with defective [G.sub.q/11][alpha] signaling leads to hyperphagia in mice

Author

Metzger, Peter J., Zhang, Aileen, Carlson, Bradley A., Sun, Hui, Cui, Zhenzhong, Li, Yongqi, Jahnke, Marshal T., Layton, Daniel R., Gupta, Meenakshi B., Liu, Naili, Kostenis, Evi, Gavrilova, Oksana, Chen, Min, and Weinstein, Lee S.

Subjects
Physiological aspects, Genetic aspects, Risk factors, Health aspects, Causes of, Hyperphagia -- Risk factors -- Genetic aspects, Neurotransmitter receptors -- Physiological aspects -- Genetic aspects, Obesity -- Risk factors -- Causes of, Melanocortins -- Physiological aspects -- Health aspects, Gene mutation -- Physiological aspects -- Health aspects, Gene mutations -- Physiological aspects -- Health aspects
Abstract

Introduction Melanocortins are neurotransmitters that act in the CNS to promote negative energy balance via reduced food intake and increased energy expenditure and sympathetic nervous system (SNS) activity. Melanocortin 4 [...], Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate [G.sub.s][alpha]/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/[G.sub.s][alpha] signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/ [G.sub.q/11][alpha] signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific [G.sub.q/11][alpha] inhibitor was delivered to the PVN; this provided evidence that a [G.sub.s][alpha]-independent signaling pathway, namely [G.sub.q/11][alpha], significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates [G.sub.q/11][alpha] may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

Published
2024
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18. A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK

Author

Feng, Xiaodong, Arang, Nadia, Rigiracciolo, Damiano Cosimo, Lee, Joo Sang, Yeerna, Huwate, Wang, Zhiyong, Lubrano, Simone, Kishore, Ayush, Pachter, Jonathan A, König, Gabriele M, Maggiolini, Marcello, Kostenis, Evi, Schlaepfer, David D, Tamayo, Pablo, Chen, Qianming, Ruppin, Eytan, and Gutkind, J Silvio

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Eye Disease and Disorders of Vision, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Animals, Cell Line, Tumor, Cell Proliferation, Computational Biology, Focal Adhesion Kinase 1, GTP-Binding Protein alpha Subunits, Gq-G11, Genes, Lethal, Hippo Signaling Pathway, Humans, Melanoma, Mice, Neoplasm Transplantation, Phosphorylation, Prognosis, Protein Serine-Threonine Kinases, Signal Transduction, Survival Analysis, Uveal Neoplasms, FAK, G protein, GNA11, GNAQ, Hippo, MOB1, PTK2, YAP, signal transduction, uveal melanoma, Protein-Serine-Threonine Kinases, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. We show that Gαq activates FAK through TRIO-RhoA non-canonical Gαq-signaling, and genetic ablation or pharmacological inhibition of FAK inhibits UM growth. Analysis of the FAK-regulated transcriptome demonstrated that GNAQ stimulates YAP through FAK. Dissection of the underlying mechanism revealed that FAK regulates YAP by tyrosine phosphorylation of MOB1, inhibiting core Hippo signaling. Our findings establish FAK as a potential therapeutic target for UM and other Gαq-driven pathophysiologies that involve unrestrained YAP function.

Published
2019

19. Gβγ signaling to the chemotactic effector P-REX1 and mammalian cell migration is directly regulated by Gαq and Gα13 proteins.

Author

Cervantes-Villagrana, Rodolfo, Adame-García, Sendi, García-Jiménez, Irving, Color-Aparicio, Víctor, Beltrán-Navarro, Yarely, König, Gabriele, Kostenis, Evi, Reyes-Cruz, Guadalupe, Gutkind, J, and Vázquez-Prado, José

Subjects
FR900359, G protein, G protein–coupled receptor (GPCR), G13, Gbetagamma, Gq, P-REX1, Ras-related C3 botulinum toxin substrate 1 (Rac1), Rho (Rho GTPase), cell migration, cell signaling, guanine nucleotide exchange factor (GEF), heterotrimeric G protein, regulator of G protein signaling (RGS), Animals, COS Cells, Cell Movement, Chlorocebus aethiops, GTP-Binding Protein alpha Subunits, G12-G13, GTP-Binding Protein alpha Subunits, Gq-G11, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Guanine Nucleotide Exchange Factors, HEK293 Cells, HeLa Cells, Humans, MCF-7 Cells, Signal Transduction
Abstract

G protein-coupled receptors stimulate Rho guanine nucleotide exchange factors that promote mammalian cell migration. Rac and Rho GTPases exert opposing effects on cell morphology and are stimulated downstream of Gβγ and Gα12/13 or Gαq, respectively. These Gα subunits might in turn favor Rho pathways by preventing Gβγ signaling to Rac. Here, we investigated whether Gβγ signaling to phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-REX1), a key Gβγ chemotactic effector, is directly controlled by Rho-activating Gα subunits. We show that pharmacological inhibition of Gαq makes P-REX1 activation by Gq/Gi-coupled lysophosphatidic acid receptors more effective. Moreover, chemogenetic control of Gi and Gq by designer receptors exclusively activated by designer drugs (DREADDs) confirmed that Gi differentially activates P-REX1. GTPase-deficient GαqQL and Gα13QL variants formed stable complexes with Gβγ, impairing its interaction with P-REX1. The N-terminal regions of these variants were essential for stable interaction with Gβγ. Pulldown assays revealed that chimeric Gα13-i2QL interacts with Gβγ unlike to Gαi2-13QL, the reciprocal chimera, which similarly to Gαi2QL could not interact with Gβγ. Moreover, Gβγ was part of tetrameric Gβγ-GαqQL-RGS2 and Gβγ-Gα13-i2QL-RGS4 complexes, whereas Gα13QL dissociated from Gβγ to interact with the PDZ-RhoGEF-RGS domain. Consistent with an integrated response, Gβγ and AKT kinase were associated with active SDF-1/CXCL12-stimulated P-REX1. This pathway was inhibited by GαqQL and Gα13QL, which also prevented CXCR4-dependent cell migration. We conclude that a coordinated mechanism prioritizes Gαq- and Gα13-mediated signaling to Rho over a Gβγ-dependent Rac pathway, attributed to heterotrimeric Gi proteins.

Published
2019

21. How Carvedilol activates β2-adrenoceptors

Author

Benkel, Tobias, Zimmermann, Mirjam, Zeiner, Julian, Bravo, Sergi, Merten, Nicole, Lim, Victor Jun Yu, Matthees, Edda Sofie Fabienne, Drube, Julia, Miess-Tanneberg, Elke, Malan, Daniela, Szpakowska, Martyna, Monteleone, Stefania, Grimes, Jak, Koszegi, Zsombor, Lanoiselée, Yann, O’Brien, Shannon, Pavlaki, Nikoleta, Dobberstein, Nadine, Inoue, Asuka, Nikolaev, Viacheslav, Calebiro, Davide, Chevigné, Andy, Sasse, Philipp, Schulz, Stefan, Hoffmann, Carsten, Kolb, Peter, Waldhoer, Maria, Simon, Katharina, Gomeza, Jesus, and Kostenis, Evi

Published
2022
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23. Selective optogenetic control of Gq signaling using human Neuropsin

Author

Wagdi, Ahmed, Malan, Daniela, Sathyanarayanan, Udhayabhaskar, Beauchamp, Janosch S., Vogt, Markus, Zipf, David, Beiert, Thomas, Mansuroglu, Berivan, Dusend, Vanessa, Meininghaus, Mark, Schneider, Linn, Kalthof, Bernd, Wiegert, J. Simon, König, Gabriele M., Kostenis, Evi, Patejdl, Robert, Sasse, Philipp, and Bruegmann, Tobias

Published
2022
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27. Heterotrimeric G Protein Subunit Gαq Is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs

Author

Pfeil, Eva Marie, Brands, Julian, Merten, Nicole, Vögtle, Timo, Vescovo, Maddalena, Rick, Ulrike, Albrecht, Ina-Maria, Heycke, Nina, Kawakami, Kouki, Ono, Yuki, Ngako Kadji, Francois Marie, Hiratsuka, Suzune, Aoki, Junken, Häberlein, Felix, Matthey, Michaela, Garg, Jaspal, Hennen, Stephanie, Jobin, Marie-Lise, Seier, Kerstin, Calebiro, Davide, Pfeifer, Alexander, Heinemann, Akos, Wenzel, Daniela, König, Gabriele M., Nieswandt, Bernhard, Fleischmann, Bernd K., Inoue, Asuka, Simon, Katharina, and Kostenis, Evi

Published
2020
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31. Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice

Author

Wenzel, Jan, Hansen, Cathrin E., Bettoni, Carla, Vogt, Miriam A., Lembrich, Beate, Natsagdorj, Rentsenkhand, Huber, Gianna, Brands, Josefine, Schmidt, Kjestine, Assmann, Julian C., Stölting, Ines, Saar, Kathrin, Sedlacik, Jan, Fiehler, Jens, Ludewig, Peter, Wegmann, Michael, Feller, Nina, Richter, Marius, Müller-Fielitz, Helge, Walther, Thomas, König, Gabriele M., Kostenis, Evi, Raasch, Walter, Hübner, Norbert, Gass, Peter, Offermanns, Stefan, de Wit, Cor, Wagner, Carsten A., and Schwaninger, Markus

Published
2020

32. WNT Stimulation Dissociates a Frizzled 4 Inactive-State Complex with Gα12/13.

Author

Arthofer, Elisa, Hot, Belma, Petersen, Julian, Strakova, Katerina, Jäger, Stefan, Grundmann, Manuel, Kostenis, Evi, Gutkind, J, and Schulte, Gunnar

Subjects
Dishevelled Proteins, Fluorescence Recovery After Photobleaching, Fluorescence Resonance Energy Transfer, Frizzled Receptors, GTP-Binding Protein alpha Subunits, G12-G13, Green Fluorescent Proteins, HEK293 Cells, Humans, Protein Binding, Protein Domains, Rho Guanine Nucleotide Exchange Factors, Signal Transduction, Wnt Proteins
Abstract

Frizzleds (FZDs) are unconventional G protein-coupled receptors that belong to the class Frizzled. They are bound and activated by the Wingless/Int-1 lipoglycoprotein (WNT) family of secreted lipoglycoproteins. To date, mechanisms of signal initiation and FZD-G protein coupling remain poorly understood. Previously, we showed that FZD6 assembles with Gαi1/Gαq (but not with Gαs, Gαo and Ga12/13), and that these inactive-state complexes are dissociated by WNTs and regulated by the phosphoprotein Dishevelled (DVL). Here, we investigated the inactive-state assembly of heterotrimeric G proteins with FZD4, a receptor important in retinal vascular development and frequently mutated in Norrie disease or familial exudative vitreoretinopathy. Live-cell imaging experiments using fluorescence recovery after photobleaching show that human FZD4 assembles-in a DVL-independent manner-with Gα12/13 but not representatives of other heterotrimeric G protein subfamilies, such as Gαi1, Gαo, Gαs, and Gαq The FZD4-G protein complex dissociates upon stimulation with WNT-3A, WNT-5A, WNT-7A, and WNT-10B. In addition, WNT-induced dynamic mass redistribution changes in untransfected and, even more so, in FZD4 green fluorescent protein-transfected cells depend on Gα12/13 Furthermore, expression of FZD4 and Gα12 or Gα13 in human embryonic kidney 293 cells induces WNT-dependent membrane recruitment of p115-RHOGEF (RHO guanine nucleotide exchange factor, molecular weight 115 kDa), a direct target of Gα12/13 signaling, underlining the functionality of an FZD4-Gα12/13-RHO signaling axis. In summary, Gα12/13-mediated WNT/FZD4 signaling through p115-RHOGEF offers an intriguing and previously unappreciated mechanistic link of FZD4 signaling to cytoskeletal rearrangements and RHO signaling with implications for the regulation of angiogenesis during embryonic and tumor development.

Published
2016

33. The Gq signalling pathway inhibits brown and beige adipose tissue

Author

Klepac, Katarina, Kilić, Ana, Gnad, Thorsten, Brown, Loren M, Herrmann, Beate, Wilderman, Andrea, Balkow, Aileen, Glöde, Anja, Simon, Katharina, Lidell, Martin E, Betz, Matthias J, Enerbäck, Sven, Wess, Jürgen, Freichel, Marc, Blüher, Matthias, König, Gabi, Kostenis, Evi, Insel, Paul A, and Pfeifer, Alexander

Subjects
Biochemistry and Cell Biology, Biological Sciences, Obesity, Nutrition, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adipocytes, Brown, Adipocytes, White, Adipogenesis, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Differentiation, GTP-Binding Protein alpha Subunits, Gq-G11, Humans, Ion Channels, Mice, Mitochondrial Proteins, Signal Transduction, Uncoupling Protein 1
Abstract

Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the Gq family, and inhibition of Gq signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of Gq signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of Gq signalling in brown adipocytes. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of Gq in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that Gq signalling regulates brown/beige adipocytes and inhibition of Gq signalling may be a novel therapeutic approach to combat obesity.

Published
2016

41. Holistic Methods for the Analysis of cNMP Effects

Author

Grundmann, Manuel, Kostenis, Evi, Barrett, James E., Editor-in-chief, Flockerzi, Veit, Series editor, Frohman, Michael A., Series editor, Geppetti, Pierangelo, Series editor, Hofmann, Franz B., Series editor, Michel, Martin C., Series editor, Page, Clive P., Series editor, Rosenthal, Walter, Series editor, Wang, KeWei, Series editor, and Seifert, Roland, editor

Published
2017
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42. Cyclic peptide inhibitors stabilize Gq/11 heterotrimers

Author

Muehle, Jonas, primary, Rodrigues, Matthew Joseph, additional, Alenfelder, Judith, additional, Juergenliemke, Lars, additional, Guixa-Gonzalez, Ramon, additional, Bacchin, Arianna, additional, Andres, Fabio, additional, Hennig, Michael, additional, Schihada, Hannes, additional, Cruesemann, Max, additional, Koenig, Gabriele, additional, Kostenis, Evi, additional, Schertler, Gebhard, additional, and Deupi, Xavier, additional

Published
2023
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