RGS4 INHIBITS G(Q)-MEDIATED ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASE AND PHOSPHOINOSITIDE SYNTHESIS

Recombinant regulators of G protein-signaling (RGS) proteins stimulate hydrolysis of GTP by a subunits of the G(i) family but have not been reported to regulate other G protein alpha subunits. Expression of rec ombinant RGS proteins in cultured cells inhibits G(i)-mediated hormona l signals probably by acting as GTPase-activating proteins for G alpha (i) subunits. To ask whether an RGS protein can also regulate cellular responses mediated by G proteins in the G(q/11) family, we compared a ctivation of mitogen-activated protein kinase (MAPK) by a G(q/11)-coup led receptor, the bombesin receptor (BR), and a G(i)-coupled receptor, the D-2 dopamine receptor, transiently co expressed with or without r ecombinant RGS4 in COS-7 cells. Pertussis toxin, which uncouples G(i) from receptors, blocked MAPK activation by the D-2 dopamine receptor b ut not by the BR. Go-expression of RGS4, however, inhibited activation of MAPK by both receptors causing a rightward shift of the concentrat ion-effect curve for both receptor agonists, RGS4 also inhibited BR-st imulated synthesis of inositol phosphates by an effector target of G(q /11), phospholipase C. Moreover, RGS4 inhibited inositol phosphate syn thesis activated by addition of AlF4- to cells overexpressing recombin ant alpha(q), probably by binding to alpha(q).GDP.AlF4-. These results demonstrate that RGS4 can regulate G(q/11)-mediated cellular signals by competing for effector binding as well as by acting as a GTPase-act ivating protein.