A large number of hormones, neurotransmitters, chemokines, local mediators, and sensory stimuli exert their effects on cells and organisms by binding to G protein-coupled receptors. More than a thousand such receptors are known, and more are being discovered all the time. Heterotrimeric G proteins transduce ligand binding to these receptors into intracellular responses, which underlie physiological responses of tissues and organisms. G proteins play important roles in determining the specificity and temporal characteristics of the cellular responses to signals. They are made up of ␣, , and ␥ subunits, and although there are many gene products encoding each subunit (20 ␣, 6 , and 12 ␥ gene products are known), four main classes of G proteins can be distinguished: G s , which activates adenylyl cyclase; G i , which inhibits adenylyl cyclase; G q , which activates phospholipase C; and G 12 and G 13 , of unknown function.G proteins are inactive in the GDP-bound, heterotrimeric state and are activated by receptor-catalyzed guanine nucleotide exchange resulting in GTP binding to the ␣ subunit. GTP binding leads to dissociation of G␣⅐GTP from G␥ subunits and activation of downstream effectors by both G␣⅐GTP and free G␥ subunits. G protein deactivation is rate-limiting for turnoff of the cellular response and occurs when the G␣ subunit hydrolyzes GTP to GDP. The recent resolution of crystal structures of heterotrimeric G proteins in inactive and active conformations provides a structural framework for understanding their role as conformational switches in signaling pathways. As more and more novel pathways that use G proteins emerge, recognition of the diversity of regulatory mechanisms of G protein signaling is also increasing. The recent progress in the structure, mechanisms, and regulation of G protein signaling pathways is the subject of this review. Because of space considerations, I will concentrate mainly on recent studies; readers are directed to a number of excellent reviews that cover earlier studies.
G Protein StructureG␣ subunits contain two domains, a domain involved in binding and hydrolyzing GTP (the G domain) that is structurally identical to the superfamily of GTPases including small G proteins and elongation factors (1) and a unique helical domain that buries the GTP in the core of the protein (2, 3) (Fig. 1). The  subunit of heterotrimeric G proteins has a 7-membered -propeller structure based on its 7 WD-40 repeats (4 -6). The ␥ subunit interacts with  through an N-terminal coiled coil and then all along the base of , making extensive contacts (Fig. 1). The  and ␥ subunits form a functional unit that is not dissociable except by denaturation. G protein activation by receptors leads to GTP binding on the G␣ subunit. The structural nature of the GTP-mediated switch on the G␣ subunit is a change in conformation of three flexible regions designated Switches I, II, and III to a well ordered, GTP-bound activated conformation with lowered affinity for G␥ (7) (Fig. 1). This leads to increased affin...