Abstract
Many Regulators of G proteinSignaling (RGS) proteins accelerate the intrinsic GTPase activity of Giα and Gqα-subunits [i.e., behave as GTPase-activating proteins (GAPs)] and several act as Gqα-effector antagonists. RGS3, a structurally distinct RGS member with a unique N-terminal domain and a C-terminal RGS domain, and an N-terminally truncated version of RGS3 (RGS3CT) both stimulated the GTPase activity of Giα (except Gzα) and Gqα but not that of Gsα or G12α. RGS3 and RGS3CT had Gqα GAP activity similar to that of RGS4. RGS3 impaired signaling through Gq-linked receptors, although RGS3CT invariably inhibited better than did full-length RGS3. RGS3 potently inhibited GqαQ209L- and G11αQ209l-mediated activation of a cAMP-response element-binding protein reporter gene and GqαQ209L induced inositol phosphate production, suggesting that RGS3 efficiently blocks Gqα from activating its downstream effector phospholipase C-β. Whereas RGS2 and to a lesser extent RGS10 also inhibited signaling by these GTPase-deficient G proteins, other RGS proteins including RGS4 did not. Mutation of residues in RGS3 similar to those required for RGS4 Giα GAP activity, as well as several residues N terminal to its RGS domain impaired RGS3 function. A greater percentage of RGS3CT localized at the cell membrane than the full-length version, 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 Giα and Gqα subfamily members and as a potent Gqα subfamily effector antagonist.
- The American Society for Pharmacology and Experimental Therapeutics
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