GAIP and RGS4 are GTPase-activating proteins for the G(i) subfamily of G protein alpha subunits

A novel class of regulators of G protein signaling (RGS) proteins has been identified recently. Genetic evidence suggests that RGS proteins inhibit G protein-mediated signaling at the level of the receptor-G protein interaction or the G protein alpha subunit itself. We have found that two RGS family members, GAlP and RGS4, are GTPase-activating proteins (GAPs), accelerating the rate of GTP hydrolysis by G(i alpha 1) at least 40-fold. All G(i) subfamily members assayed were substrates for these GAPs; (s alpha)was not. RGS4 activates the GTPase activity of certain G(i alpha 1) mutants (e.g., R178C), but not others (e.g., Q204L). The GAP activity of RGS proteins is consistent with their proposed role as negative regulators of G protein-mediated signaling.