Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer
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
Affiliations
Junke Liu
College of Life Science and Technology, Collaborative Innovation Center for Genetics and Development, and Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China
Zongyong Zhang
College of Life Science and Technology, Collaborative Innovation Center for Genetics and Development, and Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China
David Moreno-Delgado
Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, Montpellier, France
Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, Barcelona, Spain; Network Biomedical Research Center on Mental Health, Barcelona, Spain
Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, Barcelona, Spain; Network Biomedical Research Center on Mental Health, Barcelona, Spain
Qilin Yuan
College of Life Science and Technology, Collaborative Innovation Center for Genetics and Development, and Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China
College of Life Science and Technology, Collaborative Innovation Center for Genetics and Development, and Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China
College of Life Science and Technology, Collaborative Innovation Center for Genetics and Development, and Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China
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.
