Abstract
Although many G protein-coupled receptors (GPCRs) can form dimers, a possible role of this phenomenon in their activation remains elusive. A recent and exciting proposal is that a dynamic inter-subunit interplay may contribute to GPCR activation. Here we examined this possibility using a dimeric metabotropic glutamate receptor (mGluR). We first developed a system to perfectly control their subunit composition, and show that mGluR dimers do not form larger oligomers. We then examined an mGluR dimer containing one subunit in which the extracellular agonist binding domain is uncoupled from the G protein-activating transmembrane domain (TMD). Despite this uncoupling in one protomer, agonist stimulation resulted in symmetric activation of either TMD in the dimer with the same efficiency. This, plus other data, can only be explained by an inter-subunit rearrangement as the activation mechanism. Although well established for other types of receptors such as tyrosine kinase or guanylate cyclase receptors, this is the first clear demonstration that such a mechanism may also apply to GPCRs.