title: Regulator of G-protein signalling 3 redirects prototypical Gi-coupled receptors from Rac1 to RhoA activation.
abstract: The small GTPases, Rac1 and RhoA, are pivotal regulators of several essential, but distinct cellular processes. Numerous G-protein-coupled receptors signal to these GTPases, but with different specificities. Specifically, Gi-coupled receptors (GiPCRs) are generally believed to activate Rac1, but not RhoA, a process involving Gbetagamma-dimers and phosphatidylinositol 3-kinase (PI3K). Here we show that, depending on the expression level of the 519 amino acid isoform of regulator of G-protein signalling 3 (RGS3L), prototypical GiPCRs, like M2 muscarinic, A1 adenosine, and alpha2-adrenergic receptors, activate either Rac1 or RhoA in human embryonic kidney cells and neonatal rat cardiomyocyte-derived H10 cells. The switch from Rac1 to RhoA activation in H10 cells was controlled by fibroblast growth factor-2 (FGF-2), lowering the expression of RGS3L. Activation of both, Rac1 and RhoA, seen at low and high expression levels of RGS3L, respectively, was sensitive to pertussis toxin and the PI3K inhibitor LY294002 and mediated by Gbetagamma-dimers. We conclude that RGS3L functions as a molecular switch, redirecting GiPCRs via Gbetagamma-dimers and PI3K from Rac1 to RhoA activation. Considering the essential roles of Rac1 and RhoA in many signalling pathways, this additional function of RGS3L indicates a specific role of this protein in cellular signalling networks.
authors.affiliation: Department of Experimental and Clinical Pharmacology and Toxicology, University of Heidelberg, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Susanne
authors.initials: S
authors.lastname: Lutz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rümenapp
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Karl H
authors.initials: KH
authors.lastname: Jakobs
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D001216:Asparagine / Q000235:genetics; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020710:RGS Proteins; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020690:GTPase-Activating Proteins; D050505:Mutant Proteins; D020710:RGS Proteins; C485898:RGS3 protein, human; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D026362:Serum Response Factor; D016222:Fibroblast Growth Factor 2; D001216:Asparagine; D002217:Carbachol; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000409:Alanine