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

• Published in: eLife Vol. 9
• Main Authors: Laboute, Thibaut, Gandía, Jorge, Pellissier, Lucie P, Corde, Yannick, Rebeillard, Florian, Gallo, Maria, Gauthier, Christophe, Léauté, Audrey, Diaz, Jorge, Poupon, Anne, Kieffer, Brigitte L, Le Merrer, Julie, Becker, Jérôme Aj
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 31-01-2020; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: Amino acids; Analgesia; Animals; Arrestin; Behavior; beta-arrestin; beta-Arrestins - metabolism; BRET experiments; Cell Biology; Corpus Striatum - metabolism; Experiments; Female; G protein-coupled receptors; Gene expression; GPCR oligomerisation; in vitro pharmacology; in vivo pharmacology; knockout animals; Life Sciences; Ligands; Male; Mental disorders; Mice; Mice, Knockout; Morphine; Narcotics; Neostriatum; Neurons and Cognition; Neuroscience; Opioid receptors (type delta); Pain perception; Pharmacology; Physiology; Proteins; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Opioid - genetics; Receptors, Opioid - metabolism; Recruitment; Signal Transduction - genetics; Therapeutic applications; GPCR oligomerisation; mouse; knockout animals; cell biology; in vitro pharmacology; beta-arrestin; neuroscience; BRET experiments; in vivo pharmacology; HETEROMERS; PERIAQUEDUCTAL GRAY; MORPHINE; DOPAMINE; PROTEIN-COUPLED RECEPTORS; LOCOMOTOR SENSITIZATION; EXPRESSION; AGONISTS; REWARD; MICE LACKING
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.50519

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
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
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.