1. Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer
- Author
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Junke Liu, Zongyong Zhang, David Moreno-Delgado, James AR Dalton, Xavier Rovira, Ana Trapero, Cyril Goudet, Amadeu Llebaria, Jesús Giraldo, Qilin Yuan, Philippe Rondard, Siluo Huang, Jianfeng Liu, Jean-Philippe Pin, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Institute for Advanced Chemistry of Catalonia, and Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (MCS (IQAC-CSIC))
- Subjects
allostery ,QH301-705.5 ,Science ,[SDV]Life Sciences [q-bio] ,cooperativity ,G protein ,Cell Biology ,Receptors, Metabotropic Glutamate ,Rats ,Protein Subunits ,Allosteric Regulation ,Medicine ,Rat ,Animals ,metabotropic glutamate receptor ,Biology (General) ,signalling ,Protein Multimerization ,Research Article - Abstract
International audience; 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.
- Published
- 2017