Mitogenic Signaling via G Protein-Coupled Receptors

RECEPTORS coupled to heterotrimeric GTP-binding proteins (G proteins) comprise the largest known family of cell surface receptors and mediate cellular responses to a diverse array of signaling molecules, including peptide and glycopeptide hormones, neurotransmitters, phospholipids, odorants, and photons. The basic unit of G protein-coupled receptor (GPCR) signaling is comprised of three parts; receptor, which detects ligand in the extracellular milieu; heterotrimeric G protein, which is dissociated into active Gα-GTP and Gβγ-subunits after interaction with the liganded receptor; and effector, which interacts with dissociated Gα-GTP and Gβγ-subunits to mediate the intracellular effects of ligand binding. In a given cell type, the responsiveness to stimulus, as well as the nature of the response, is dictated by the available complement of receptor, G protein, and effector. Despite the diverse array of ligands with which they interact, GPCRs share a conserved predicted tertiary structure characterized by seven transmembrane domains joined by intracellular and extracellular loops. G protein coupling specificity is dictated by the intracellular domains, particularly the second and third intracellular loops and the Cterminal tail. Indeed, it is possible to alter the G proteincoupling specificity of GPCRs by exchanging relatively small regions within the third intracellular loop (1).