Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling
| Autor: | Jean-Louis Banères, Lauriane Onfroy, Jean-Philippe Leyris, Mathieu Maingot, Pascal Verdié, Jean Martinez, Aude Saulière, Céline Galés, Marjorie Damian, Jean-Alain Fehrentz, Céline M'Kadmi, Didier Gagne, Séverine Denoyelle, Jacky Marie, Sophie Mary |
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| Přispěvatelé: | 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), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Herrada, Anthony |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
MESH: Signal Transduction
Arrestins Pharmacology MESH: Drug Design Ligands Biochemistry GHS-R1a homogenous time resolved fluorescence MESH: Receptors Ghrelin GPCR MESH: Structure-Activity Relationship [CHIM] Chemical Sciences MESH: Ligands Receptor Receptors Ghrelin beta-Arrestins bioluminescence resonance energy transfer (BRET) ANOVA MESH: Kinetics GTP␥S Growth hormone secretion GH MESH: GTP-Binding Protein alpha Subunits Gq-G11 ghrelin MESH: HEK293 Cells signaling bias bioluminescence resonance energy transfer SRE MESH: Arrestins Signal transduction HTRF hormones hormone substitutes and hormone antagonists Signal Transduction serum-responsive element Cell signaling analysis of variance MESH: GTP-Binding Proteins inositol phosphate G protein MAP Kinase Signaling System Inositol Phosphates G protein-coupled receptor (GPCR) G protein subtypes Biology Structure-Activity Relationship GTP-binding protein regulators MESH: beta-Arrestins GTP-Binding Proteins guanosine 5Ј-O-(3-thiotriphosphate) mental disorders Arrestin Inverse agonist Humans cell signaling [CHIM]Chemical Sciences G protein-coupled receptor Molecular Biology substance P analog growth hormone secretagogue receptor type 1a MESH: Humans MESH: MAP Kinase Signaling System IP1 Cell Biology hormone receptor MESH: Inositol Phosphates Kinetics HEK293 Cells inositol 1-phosphate Drug Design IP growth hormone GTP-Binding Protein alpha Subunits Gq-G11 BRET SPA |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, 2015, 290 (45), pp.27021-27039. ⟨10.1074/jbc.M115.659250⟩ |
| ISSN: | 0021-9258 1083-351X |
| DOI: | 10.1074/jbc.M115.659250⟩ |
| Popis: | International audience; The G protein-coupled receptor GHS-R1a mediates ghrelin-induced growth hormone secretion, food intake, and reward-seeking behaviors. GHS-R1a signals through Gq, Gi/o, G13, and arrestin. Biasing GHS-R1a signaling with specific ligands may lead to the development of more selective drugs to treat obesity or addiction with minimal side effects. To delineate ligand selectivity at GHS-R1a signaling, we analyzed in detail the efficacy of a panel of synthetic ligands activating the different pathways associated with GHS-R1a in HEK293T cells. Besides β-arrestin2 recruitment and ERK1/2 phosphorylation, we monitored activation of a large panel of G protein subtypes using a bioluminescence resonance energy transfer-based assay with G protein-activation biosensors. We first found that unlike full agonists, Gq partial agonists were unable to trigger β-arrestin2 recruitment and ERK1/2 phosphorylation. Using G protein-activation biosensors, we then demonstrated that ghrelin promoted activation of Gq, Gi1, Gi2, Gi3, Goa, Gob, and G13 but not Gs and G12. Besides, we identified some GHS-R1a ligands that preferentially activated Gq and antagonized ghrelin-mediated Gi/Go activation. Finally, we unambiguously demonstrated that in addition to Gq, GHS-R1a also promoted constitutive activation of G13. Importantly, we identified some ligands that were selective inverse agonists toward Gq but not of G13. This demonstrates that bias at GHS-R1a signaling can occur not only with regard to agonism but also to inverse agonism. Our data, combined with other in vivo studies, may facilitate the design of drugs selectively targeting individual signaling pathways to treat only the therapeutically relevant function. |
| Databáze: | OpenAIRE |
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