Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer
- Huazhong University of Science and Technology, China
- CNRS, INSERM, Univ. Montpellier, France
- Universitat Autònoma de Barcelona (UAB), Spain
- Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Spain
- Universitat Autònoma de Barcelona (UAB), Spain
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.
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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.
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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Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer
eLife 6:e26985.
https://doi.org/10.7554/eLife.26985
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