Role for G12/G13 in agonist-induced vascular smooth muscle cell contraction

Receptor-induced vascular smooth muscle cell contraction is mediated by dual regulation of myosin light chain (MLC20) phosphorylation through Ca2+-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 MLC20 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 G alpha(12) and G alpha(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 G alpha(12) and G alpha(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 MLC20 phosphorylation by vasocontractors is initiated by the dual coupling of their receptors to G proteins of the G(q) and G(12) families.