Role for G 12 /G 13 in Agonist-Induced Vascular Smooth Muscle Cell Contraction

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Abstract
—Receptor-induced vascular smooth muscle cell contraction is mediated by dual regulation of myosin light chain (MLC 20 ) phosphorylation through Ca 2+ -dependent stimulation of myosin light chain kinase and Rho/Rho-kinase–mediated inhibition of myosin phosphatase. Although myosin light chain kinase regulation is initiated by the coupling of receptors to G proteins of the G q family, G q and G 11 , it is not known how receptors regulate the Rho/Rho-kinase–mediated pathway. In vascular smooth muscle cells, receptor-mediated MLC 20 phosphorylation and cell contraction was blocked by inhibitors of each of the pathways. Receptors of various vasocontractors were found to couple to G q /G 11 and G 12 /G 13 , and constitutively active forms of Gα 12 and Gα 13 induced a pronounced contraction of vascular smooth muscle cells that could be blocked by C3 exoenzyme, by inhibition of Rho-kinase, and by stable analogues of cGMP and cAMP. Receptor-mediated smooth muscle cell contraction was strongly inhibited by dominant-negative forms of Gα 12 and Gα 13 . These data indicate that a G 12 /G 13 -mediated Rho/Rho-kinase–dependent pathway operates in smooth muscle cells and that dual regulation of MLC 20 phosphorylation by vasocontractors is initiated by the dual coupling of their receptors to G proteins of the G q and G 12 families.