A model for the functioning of family 3 GPCRs.

Family 3 G-protein-coupled receptors (GPCRs) comprise the metabotropic glutamate (mglu) receptors, GABA(B) receptors, Ca(2+)-sensing receptors and some taste and putative pheromone receptors. All are composed of two domains, an extracellular ligand-binding domain and a transmembrane heptahelical domain that activates G proteins. Here we propose a model for the function of family 3 GPCRs that takes into account their structure. This model fits with specific pharmacological features of some family 3 GPCRs, such as modulation by positive and negative allosteric regulators. The model also reveals differences between GABA(B) receptors and Group I mglu receptors: in the former there is "tight" functional coupling between the two domains of the receptor whereas the "loose" coupling in the latter gives these receptors specific features not shared by many other GPCRs.