RGS3 is a GTPase-activating protein for G(i alpha) and G(q alpha) and a potent inhibitor of signaling by GTPase-deficient forms of G(q alpha) and G(11 alpha)

Many Regulators of G protein Signaling (RGS) proteins accelerate the intrin sic GTPase activity of G(ia) and G(q alpha)-subunits [i.e., behave as GTPas e-activating proteins (GAPs)] and several act as G(q alpha)-effector antago nists. RGS3, a structurally distinct RGS member with a unique N-terminal do main and a C-terminal RGS domain, and an N-terminally truncated version of RGS3 (RGS3CT) both stimulated the GTPase activity of G(i alpha) (except G(z alpha)) and G(q alpha) but not that of G(s alpha) or G(12 alpha). RGS3 and RGS3CT had G(q alpha) GAP activity similar to that of RGS4. RGS3 impaired signaling through G(q)-linked receptors, although RGS3CT invariably inhibit ed better than did full-length RGS3. RGS3 potently inhibited G(q alpha)Q209 L- and G(11 alpha)Q209L-mediated activation of a cAMP-response element-bind ing protein reporter gene and G(q alpha)Q209L induced inositol phosphate pr oduction, suggesting that RGS3 efficiently blocks G(q alpha) from activatin g its downstream effector phospholipase C-beta. Whereas RGS2 and to a lesse r extent RGS10 also inhibited signaling by these GTPase-deficient G protein s, other RGS proteins including RGS4 did not. Mutation of residues in RGS3 similar to those required for RGS4 G(i alpha) GAP activity, as well as seve ral residues N terminal to its RGS domain impaired RGS3 function. A greater percentage of RGS3CT localized at the cell membrane than the full-length v ersion, potentially explaining why RGS3CT blocked signaling better than did full-length RGS3. Thus, RGS3 can impair Gi- (but not Gz-) and Gq-mediated signaling in hematopoietic and other cell types by acting as a GAP for G(i alpha) and G(q alpha) subfamily members and as a potent G(q alpha) subfamil y effector antagonist.