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

Elife. 2020 Jan 31:9:e50519. 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 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.

Keywords: BRET experiments; GPCR oligomerisation; beta-arrestin; cell biology; in vitro pharmacology; in vivo pharmacology; knockout animals; mouse; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / metabolism*
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Receptors, Opioid / genetics
  • Receptors, Opioid / metabolism*
  • Signal Transduction / genetics*
  • beta-Arrestins / metabolism


  • Gpr88 protein, mouse
  • Receptors, G-Protein-Coupled
  • Receptors, Opioid
  • beta-Arrestins