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

0301 basic medicine allostery QH301-705.5 [SDV]Life Sciences [q-bio] cooperativity Science Q mGlu receptor R G protein Cell Biology Receptors, Metabotropic Glutamate Rats Protein Subunits 03 medical and health sciences Allosteric Regulation Schizophrenia Rat Medicine Animals metabotropic glutamate receptor signalling Biology (General) Protein Multimerization
DOI: 10.7554/elife.26985 Publication Date: 2017-08-10T12:00:08Z
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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