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Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer

  1. Junke Liu
  2. Zongyong Zhang
  3. David Moreno-Delgado
  4. James Dalton
  5. Xavier Rovira
  6. Ana Trapero
  7. Cyril Goudet
  8. Amadeu Llebaria
  9. Jesús Giraldo
  10. Qilin Yuan
  11. Philippe Rondard
  12. Siluo Huang  Is a corresponding author
  13. Jianfeng Liu  Is a corresponding author
  14. Jean-Philippe Pin  Is a corresponding author
  1. Huazhong University of Science and Technology, China
  2. CNRS, INSERM, Univ. Montpellier, France
  3. Universitat Autònoma de Barcelona (UAB), Spain
  4. Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Spain
  5. Universitat Autònoma de Barcelona (UAB), Spain
Research Article
  • Cited 15
  • Views 2,158
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Cite this article as: eLife 2017;6:e26985 doi: 10.7554/eLife.26985

Abstract

GPCRs play critical roles in cell communication. Although GPCRs can form heteromers, their role in signaling remains elusive. Here we used rat metabotropic glutamate (mGlu) receptors as prototypical dimers to study the functional interaction between each subunit. mGluRs can form both constitutive homo- and heterodimers. Whereas both mGlu2 and mGlu4 couple to G proteins, G protein activation is mediated by mGlu4 heptahelical domain (HD) exclusively in mGlu2-4 heterodimers. Such asymmetric transduction results from the action of both the dimeric extracellular domain, and an allosteric activation by the partially-activated non-functional mGlu2 HD. G proteins activation by mGlu2 HD occurs if either the mGlu2 HD is occupied by a positive allosteric modulator or if mGlu4 HD is inhibited by a negative modulator. These data revealed an oriented asymmetry in mGlu heterodimers that can be controlled with allosteric modulators. They provide new insight on the allosteric interaction between subunits in a GPCR dimer.

Article and author information

Author details

  1. Junke Liu

    Sino-France Laboratory of Cellular Signaling, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Zongyong Zhang

    Sino-France Laboratory of Cellular Signaling, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  3. David Moreno-Delgado

    Institut de Génomique Fonctionnelle (IGF), CNRS, INSERM, Univ. Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  4. James Dalton

    Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5279-4581
  5. Xavier Rovira

    Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9764-9927
  6. Ana Trapero

    MCS, Laboratory of Medicinal Chemistry and Synthesis, Institute for Advanced Chemistry of Catalonia, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Cyril Goudet

    Institut de Génomique Fonctionnelle (IGF), CNRS, INSERM, Univ. Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8255-3535
  8. Amadeu Llebaria

    MCS, Laboratory of Medicinal Chemistry and Synthesis, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8200-4827
  9. Jesús Giraldo

    Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7082-4695
  10. Qilin Yuan

    Sino-France Laboratory of Cellular Signaling, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Philippe Rondard

    Institut de Génomique Fonctionnelle (IGF), CNRS, INSERM, Univ. Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1134-2738
  12. Siluo Huang

    Sino-France Laboratory of Cellular Signaling, Huazhong University of Science and Technology, Wuhan, China
    For correspondence
    slhuang@mail.hust.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Jianfeng Liu

    Sino-France Laboratory of Cellular Signaling, Huazhong University of Science and Technology, Wuhan, China
    For correspondence
    jfliu@mail.hust.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0284-8377
  14. Jean-Philippe Pin

    Institut de Génomique Fonctionnelle (IGF), CNRS, INSERM, Univ. Montpellier, Montpellier, France
    For correspondence
    jppin@igf.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1423-345X

Funding

National Natural Science Foundation of China (31420103909)

  • Jianfeng Liu

National Natural Science Foundation of China (31100548)

  • Siluo Huang

The program of introducing talents of discipline to the university of the ministry of education of China (B08029)

  • Jianfeng Liu

Mérieux research grants program

  • Jianfeng Liu

Centre National de la Recherche Scientifique

  • Jean-Philippe Pin

Institut National de la Santé et de la Recherche Médicale

  • Jean-Philippe Pin

Fondation pour la Recherche Médicale (DEQ20130326522)

  • Jean-Philippe Pin

National Natural Science Foundation of China (31711530146)

  • Jianfeng Liu

National Natural Science Foundation of China (31511130131)

  • Jianfeng Liu

Natural Science Foundation of Hubei Province (2014CFA010)

  • Junke Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lucy Forrest, NINDS, United States

Publication history

  1. Received: March 20, 2017
  2. Accepted: August 3, 2017
  3. Accepted Manuscript published: August 10, 2017 (version 1)
  4. Accepted Manuscript updated: August 11, 2017 (version 2)
  5. Accepted Manuscript updated: August 11, 2017 (version 3)
  6. Version of Record published: August 22, 2017 (version 4)
  7. Version of Record updated: September 4, 2017 (version 5)

Copyright

© 2017, Liu 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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