1. The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs.
- Author
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Laboute T, Gandía J, Pellissier LP, Corde Y, Rebeillard F, Gallo M, Gauthier C, Léauté A, Diaz J, Poupon A, Kieffer BL, Le Merrer J, and Becker JA
- Subjects
- Animals, Female, Male, Mice, Mice, Knockout, Receptors, Opioid genetics, beta-Arrestins metabolism, Corpus Striatum metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Receptors, Opioid metabolism, Signal Transduction genetics
- Abstract
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., Competing Interests: TL, JG, LP, YC, FR, MG, CG, AL, JD, AP, BK, JL, JB No competing interests declared, (© 2020, Laboute et al.)
- Published
- 2020
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