INHIBITION OF BRAIN G(Z) GAP AND OTHER RGS PROTEINS BY PALMITOYLATIONOF G-PROTEIN ALPHA-SUBUNITS

Palmitoylation of the alpha subunit of the guanine nucleotide-binding protein G(z) inhibited by more than 90 percent its response to the gua nosine triphosphatase (GTPase)-accelerating activity of G(z) GAP, a G( z)-selective member of the regulators of G-protein signaling (RGS) pro tein family of GTPase-activating proteins (GAPs). Palmitoylation both decreased the affinity of G(z) GAP for the GTP-bound form of G alpha(z ) by at least 90 percent and decreased the maximum rate of GTP hydroly sis. Inhibition was reversed by removal of the palmitoyl group by dith iothreitol. Palmitoylation of G alpha(z) also inhibited its response t o the GAP activity of G alpha-interacting protein (GAIP), another RGS protein, and palmitoylation of G alpha(l1) inhibited ils response to R GS4. The extent of inhibition of G(z) GAP, GAIP, RGS4, and RGS10 corre lated roughly with their intrinsic GAP activities for the G alpha targ et used in the assay. Reversible palmitoylation is thus a major determ inant of G(z) deactivation after its stimulation by receptors, and may be a general mechanism for prolonging or potentiating G-protein signa ling.