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

  1. Thibaut Laboute
  2. Jorge Gandía
  3. Lucie P Pellissier
  4. Yannick Corde
  5. Florian Rebeillard
  6. Maria Gallo
  7. Christophe Gauthier
  8. Audrey Léauté
  9. Jorge Diaz
  10. Anne Poupon
  11. Brigitte L Kieffer
  12. Julie Le Merrer  Is a corresponding author
  13. Jérôme AJ Becker  Is a corresponding author
  1. INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, France
  2. Inserm, France
  3. Pompeu Fabra University, Spain
  4. 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

  1. Thibaut Laboute

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0870-1891
  2. Jorge Gandía

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1711-8075
  3. Lucie P Pellissier

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Yannick Corde

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Florian Rebeillard

    Cellular Biology and Molecular Pharmacology of Central Receptors, Inserm, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Maria Gallo

    Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Christophe Gauthier

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Audrey Léauté

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Jorge Diaz

    Cellular Biology and Molecular Pharmacology of Central Receptors, Inserm, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Anne Poupon

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Brigitte L Kieffer

    Department of Psychiatry, McGill University, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8809-8334
  12. Julie Le Merrer

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    For correspondence
    julie.le-merrer@inra.fr
    Competing interests
    The authors declare that no competing interests exist.
  13. Jérôme AJ Becker

    Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours, Inserm, Nouzilly, France
    For correspondence
    jerome.becker@inra.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0039-0067

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

  1. Volker Dötsch, Goethe University, Germany

Publication history

  1. Received: July 25, 2019
  2. Accepted: January 30, 2020
  3. Accepted Manuscript published: January 31, 2020 (version 1)
  4. 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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  1. Thibaut Laboute
  2. Jorge Gandía
  3. Lucie P Pellissier
  4. Yannick Corde
  5. Florian Rebeillard
  6. Maria Gallo
  7. Christophe Gauthier
  8. Audrey Léauté
  9. Jorge Diaz
  10. Anne Poupon
  11. Brigitte L Kieffer
  12. Julie Le Merrer
  13. Jérôme AJ Becker
(2020)
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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