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

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 beta-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 mOR 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 beta-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.
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Submitted on : Wednesday, November 11, 2020 - 3:26:52 PM
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Thibaut Laboute, Jorge Gandía, Lucie P. Pellissier, Yannick Corde, Florian Rebeillard, et al.. The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs. eLife, eLife Sciences Publication, 2020, 9, ⟨10.7554/eLife.50519⟩. ⟨hal-02898979⟩

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