Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators

摘要

The recent discovery of positive allosteric modulators (PAMs) for G-protein coupled receptors (GPCRs) open new possibilities to control a number of physiological and pathological processes. Understanding the mechanism of action of such compounds will provide new information on the activation process of these important receptors. Within the last 10 years, a number of studies indicate that GPCRs can form dimers, but the functional significance of this phenomena remains elusive. Here we used the metabotropic glutamate receptors as a model since these receptors, for which PAMs have been identified, are constitutive dimers. We used the quality control system of the GABAB receptor to generate mGlu dimers in which a single subunit binds a PAM. We show that one PAM per dimer is sufficient to enhance receptor activity. Such a potentiation can still be observed if the subunit unable to bind the PAM is also made unable to activate G-proteins. However, the PAM acts as a non competitive antagonist when it binds in the subunit that cannot activate G-proteins. These data are consistent with a single heptahelical domain reaching the active state per dimer during receptor activation.