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Elife. 2020 Jan 31;9. pii: e50519. doi: 10.7554/eLife.50519. [Epub ahead of print]

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

Author information

1
Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France.
2
Cellular Biology and Molecular Pharmacology of Central Receptors, Inserm, Paris, France.
3
Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain.
4
Department of Psychiatry, McGill University, Montréal, Canada.

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 b-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 b-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.

KEYWORDS:

cell biology; mouse; neuroscience

PMID:
32003745
DOI:
10.7554/eLife.50519
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