RGS2/G0S8 is a selective inhibitor of Gqα function

RGS (regulators of G protein signaling) proteins are GTPase activating proteins that inhibit signaling by heterotrimeric G proteins. All RGS proteins studied to date act on members of the Gi alpha family, but not Gs alpha or G12 alpha. RGS4 regulates Gi alpha family members and Gq alpha. RGS2 (G0S8) is exceptional because the G proteins it regulates have not been identified. We report that RGS2 is a selective and potent inhibitor of Gq alpha function. RGS2 selectively binds Gq alpha, but not other G alpha proteins (Gi, Go, Gs, G12/13) in brain membranes; RGS4 binds Gq alpha and Gi alpha family members. RGS2 binds purified recombinant Gq alpha, but not Go alpha, whereas RGS4 binds either. RGS2 does not stimulate the GTPase activities of Gs alpha or Gi alpha family members, even at a protein concentration 3000-fold higher than is sufficient to observe effects of RGS4 on Gi alpha family members. In contrast, RGS2 and RGS4 completely inhibit Gq-directed activation of phospholipase C in cell membranes. When reconstituted with phospholipid vesicles, RGS2 is 10-fold more potent than RGS4 in blocking Gq alpha-directed activation of phospholipase C beta 1. These results identify a clear physiological role for RGS2, and describe the first example of an RGS protein that is a selective inhibitor of Gq alpha function.