Role for G(12)/G(13) in agonist-induced vascular smooth muscle cell contraction.
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 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 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.
Institut für Pharmakologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany.
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Gohla
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Schultz
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Offermanns
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002417:Cattle; D019332:Endothelin-1 / Q000494:pharmacology*; D051960:GTP-Binding Protein alpha Subunit, Gi2; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D019332:Endothelin-1; D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D011518:Proto-Oncogene Proteins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D051960:GTP-Binding Protein alpha Subunit, Gi2; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein