Activation mechanism of the heterodimeric GABA B receptor

Abstract

The GABA B receptor was the first heteromeric G-protein coupled receptor (GPCR) identified. Indeed, both GABA B1 and GABA B2 subunits appear necessary to get a functional GABA B receptor. Soon after the cloning of both subunits, it was demonstrated that GABA B2 was required for GABA B1 to reach the cell surface. However, even a mutated GABA B1 able to reach the cell surface is not functional alone despite its ability to bind GABA B ligands. This clearly demonstrated that GABA B2 is not only required for the correct trafficking of GABA B1 but also for the correct functioning of the receptor. In the present review article, we will summarize our actual knowledge of the specific role of each subunit in ligand recognition, intramolecular transduction, G-protein activation and allosteric modulation. We will show that the GABA B receptor is an heterodimer (not an hetero-oligomer), that agonists bind in GABA B1, whereas GABA B2 controls agonist affinity and is responsible for G-protein coupling. Finally, we will show that the recently identified positive allosteric modulator CGP7930 acts as a direct activator of the heptahelical domain of GABA B2, being therefore the first GABA B2 ligand identified so far.