RGS4 inhibits Gq-mediated activation of mitogen-activated protein kinase and phosphoinositide synthesis.
Recombinant regulators of G protein-signaling (RGS) proteins stimulate hydrolysis of GTP by alpha subunits of the Gi family but have not been reported to regulate other G protein alpha subunits. Expression of recombinant RGS proteins in cultured cells inhibits Gi-mediated hormonal signals probably by acting as GTPase-activating proteins for Galphai subunits. To ask whether an RGS protein can also regulate cellular responses mediated by G proteins in the Gq/11 family, we compared activation of mitogen-activated protein kinase (MAPK) by a Gq/11-coupled receptor, the bombesin receptor (BR), and a Gi-coupled receptor, the D2 dopamine receptor, transiently co-expressed with or without recombinant RGS4 in COS-7 cells. Pertussis toxin, which uncouples Gi from receptors, blocked MAPK activation by the D2 dopamine receptor but not by the BR. Co-expression of RGS4, however, inhibited activation of MAPK by both receptors causing a rightward shift of the concentration-effect curve for both receptor agonists. RGS4 also inhibited BR-stimulated synthesis of inositol phosphates by an effector target of Gq/11, phospholipase C. Moreover, RGS4 inhibited inositol phosphate synthesis activated by addition of AlF4- to cells overexpressing recombinant alphaq, probably by binding to alphaq.GDP.AlF4-. These results demonstrate that RGS4 can regulate Gq/11-mediated cellular signals by competing for effector binding as well as by acting as a GTPase-activating protein.
Yan
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Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143-0450, USA.
Chi
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Bourne
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D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D020710:RGS Proteins; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D017607:Aluminum Compounds; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011506:Proteins; D020710:RGS Proteins; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; C098799:RGS4 protein; D019257:Quinpirole; C050992:tetrafluoroaluminate; D037342:Pertussis Toxin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D001839:Bombesin; D005459:Fluorides