The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
- INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, France
- Inserm, France
- Pompeu Fabra University, Spain
- McGill University, 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Brigitte L Kieffer
Funding
Region Centre-Val de Loire (ARD2020 Biomedicaments - GPCRAb)
- Julie Le Merrer
- Jérôme AJ Becker
LabEX MAbImprove
- Julie Le Merrer
- Jérôme AJ Becker
Fonds Unique Interministériel (ATHOS)
- Brigitte L Kieffer
- Julie Le Merrer
- Jérôme AJ Becker
Marie-Curie/AgreeSkills Program (Postdoctoral Fellowshio)
- Lucie P Pellissier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental procedures were conducted in accordance with the European Communities Council Directive 2010/63/EU and approved by the Comité d'Ethique pour l'Expérimentation Animale de l'ICS et de l'IGBMC (Com'Eth, 2012-047)
Reviewing Editor
- Volker Dötsch, Goethe University, Germany
Publication history
- Received: July 25, 2019
- Accepted: January 30, 2020
- Accepted Manuscript published: January 31, 2020 (version 1)
- Version of Record published: February 11, 2020 (version 2)
Copyright
© 2020, Laboute et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
eLife 9:e50519.
https://doi.org/10.7554/eLife.50519
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