The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs

GPR88 is an orphan G protein-coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders; its pharmacology, however, remains scarcely understood. Based on our previous report of increased delta opioid receptor activity in Gpr88 null mice, we investigated the i...

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Main Authors:	Thibaut Laboute, Jorge Gandía, Lucie P Pellissier, Yannick Corde, Florian Rebeillard, Maria Gallo, Christophe Gauthier, Audrey Léauté, Jorge Diaz, Anne Poupon, Brigitte L Kieffer, Julie Le Merrer, Jérôme AJ Becker
Format:	Article
Language:	English
Published:	eLife Sciences Publications Ltd 2020-01-01
Series:	eLife
Subjects:	in vitro pharmacology BRET experiments beta-arrestin GPCR oligomerisation knockout animals in vivo pharmacology
Online Access:	https://elifesciences.org/articles/50519

id	doaj-68fc1b1b72044d1da177f37a7c4ff79f
record_format	Article
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Thibaut Laboute Jorge Gandía Lucie P Pellissier Yannick Corde Florian Rebeillard Maria Gallo Christophe Gauthier Audrey Léauté Jorge Diaz Anne Poupon Brigitte L Kieffer Julie Le Merrer Jérôme AJ Becker
spellingShingle	Thibaut Laboute Jorge Gandía Lucie P Pellissier Yannick Corde Florian Rebeillard Maria Gallo Christophe Gauthier Audrey Léauté Jorge Diaz Anne Poupon Brigitte L Kieffer Julie Le Merrer Jérôme AJ Becker The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs eLife in vitro pharmacology BRET experiments beta-arrestin GPCR oligomerisation knockout animals in vivo pharmacology
author_facet	Thibaut Laboute Jorge Gandía Lucie P Pellissier Yannick Corde Florian Rebeillard Maria Gallo Christophe Gauthier Audrey Léauté Jorge Diaz Anne Poupon Brigitte L Kieffer Julie Le Merrer Jérôme AJ Becker
author_sort	Thibaut Laboute
title	The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
title_short	The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
title_full	The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
title_fullStr	The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
title_full_unstemmed	The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
title_sort	orphan receptor gpr88 blunts the signaling of opioid receptors and multiple striatal gpcrs
publisher	eLife Sciences Publications Ltd
series	eLife
issn	2050-084X
publishDate	2020-01-01
description	GPR88 is an orphan G protein-coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders; its pharmacology, however, remains scarcely understood. Based on our previous report of increased delta opioid receptor activity in Gpr88 null mice, we investigated the impact of GPR88 co-expression on the signaling of opioid receptors in vitro and revealed that GPR88 inhibits the activation of both their G protein- and β-arrestin-dependent signaling pathways. In Gpr88 knockout mice, morphine-induced locomotor sensitization, withdrawal and supra-spinal analgesia were facilitated, consistent with a tonic inhibitory action of GPR88 on µOR signaling. We then explored GPR88 interactions with more striatal versus non-neuronal GPCRs, and revealed that GPR88 can decrease the G protein-dependent signaling of most receptors in close proximity, but impedes β-arrestin recruitment by all receptors tested. Our study unravels an unsuspected buffering role of GPR88 expression on GPCR signaling, with intriguing consequences for opioid and striatal functions.
topic	in vitro pharmacology BRET experiments beta-arrestin GPCR oligomerisation knockout animals in vivo pharmacology
url	https://elifesciences.org/articles/50519
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spelling	doaj-68fc1b1b72044d1da177f37a7c4ff79f2021-05-05T20:47:19ZengeLife Sciences Publications LtdeLife2050-084X2020-01-01910.7554/eLife.50519The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRsThibaut Laboute0https://orcid.org/0000-0003-0870-1891Jorge Gandía1https://orcid.org/0000-0003-1711-8075Lucie P Pellissier2Yannick Corde3Florian Rebeillard4Maria Gallo5Christophe Gauthier6Audrey Léauté7Jorge Diaz8Anne Poupon9Brigitte L Kieffer10https://orcid.org/0000-0002-8809-8334Julie Le Merrer11https://orcid.org/0000-0002-8670-4273Jérôme AJ Becker12https://orcid.org/0000-0002-0039-0067Deficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, FranceDeficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, FranceDeficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France; Biology and Bioinformatics of Signalling Systems, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Nouzilly, FranceDeficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, FranceCellular Biology and Molecular Pharmacology of central Receptors, Centre de Psychiatrie et Neurosciences, Inserm UMR_S894 - Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceDepartment of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Barcelona, SpainBiology and Bioinformatics of Signalling Systems, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Nouzilly, FranceDeficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, FranceCellular Biology and Molecular Pharmacology of central Receptors, Centre de Psychiatrie et Neurosciences, Inserm UMR_S894 - Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceBiology and Bioinformatics of Signalling Systems, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Nouzilly, FranceDepartment of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Canada; Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U1258, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, FranceDeficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U1258, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, FranceDeficits of Reward GPCRs and Sociability, Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U1258, Université de Strasbourg, 1 rue Laurent Fries, Illkirch, FranceGPR88 is an orphan G protein-coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders; its pharmacology, however, remains scarcely understood. Based on our previous report of increased delta opioid receptor activity in Gpr88 null mice, we investigated the impact of GPR88 co-expression on the signaling of opioid receptors in vitro and revealed that GPR88 inhibits the activation of both their G protein- and β-arrestin-dependent signaling pathways. In Gpr88 knockout mice, morphine-induced locomotor sensitization, withdrawal and supra-spinal analgesia were facilitated, consistent with a tonic inhibitory action of GPR88 on µOR signaling. We then explored GPR88 interactions with more striatal versus non-neuronal GPCRs, and revealed that GPR88 can decrease the G protein-dependent signaling of most receptors in close proximity, but impedes β-arrestin recruitment by all receptors tested. Our study unravels an unsuspected buffering role of GPR88 expression on GPCR signaling, with intriguing consequences for opioid and striatal functions.https://elifesciences.org/articles/50519in vitro pharmacologyBRET experimentsbeta-arrestinGPCR oligomerisationknockout animalsin vivo pharmacology

The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs

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