GAIP and RGS4 Are GTPase-Activating Proteins for the Gi Subfamily of G Protein α Subunits

terized G protein GAP is phospholipase C-b, which is Summary both a GAP for Gqa and the effector that is activated by that G protein (Berstein et al., 1992; Biddlecome et al., A novel class of regulators of G protein signaling (RGS) 1996). The GTPase activity of the a subunit of transducin proteins has been identified recently. Genetic eviis also stimulated by its effector, the g subunit of a retinal dence suggests that RGS proteins inhibit G protein– cyclic GMP–specific phosphodiesterase (Arshavsky and mediated signaling at the level of the receptor–G proBownds, 1992), as well as by a second unidentified protein interaction or the G protein a subunit itself. We tein (Angleson and Wensel, 1993; Pages et al., 1993; have found that two RGS family members, GAIP and Arshavsky et al., 1994). RGS4, are GTPase-activating proteins (GAPs), accelA novel family of putative regulators of G protein sigerating the rate of GTP hydrolysis by Gia1 at least 40naling (RGS) has been identified recently, predominantly fold. All Gi subfamily members assayed were subby genetic techniques (Roush, 1996). Evidence suggests strates for these GAPs; Gsa was not. RGS4 activates that these proteins suppress G protein signaling by acthe GTPase activity of certain Gia1 mutants (e.g., tions at the level of the a subunit or the interaction R178C), but not others (e.g., Q204L). The GAP activity between receptor and G protein. Notably, mutations in of RGS proteins is consistent with their proposed role the SST2 (supersensitivity to pheromone) gene in Sacas negative regulators of G protein–mediated sigcharomyces cerevisiae result in unchecked G protein– naling. mediated signaling in response to pheromone (Chan