Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II.
We here review mechanisms that can regulate the activity of myosin II, in smooth muscle and non-muscle cells, by modulating the Ca2+ sensitivity of myosin regulatory light chain (RLC) phosphorylation. The major mechanism of Ca2+ sensitization of smooth muscle contraction and non-muscle cell motility is through inhibition of the smooth muscle myosin phosphatase (MLCP) that dephosphorylates the RLC in smooth muscle and non-muscle. The active, GTP-bound form of the small GTPase RhoA activates a serine/threonine kinase, Rho-kinase, that phosphorylates the regulatory subunit of MLCP and inhibits phosphatase activity. G-protein-coupled release of arachidonic acid may also contribute to inhibition of MLCP acting, at least in part, through the Rho/Rho-kinase pathway. Protein kinase C(s) activated by phorbol esters and diacylglycerol can also inhibit MLCP by phosphorylating and thereby activating CPI-17, an inhibitor of its catalytic subunit; this mechanism is independent of the Rho/Rho-kinase pathway and plays only a minor, transient role in the G-protein-coupled mechanism of Ca2+ sensitization. Ca2+ sensitization by the Rho/Rho-kinase pathway contributes to the tonic phase of agonist-induced contraction in smooth muscle, and abnormally increased activation of myosin II by this mechanism is thought to play a role in diseases such as high blood pressure and cancer cell metastasis.
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Departments of Molecular Physiology and Biological Physics, Medicine (Cardiology) and Pathology, University of Virginia Health System, PO Box 800736, Charlottesville, VA 22908-0736, USA. aps2n@virginia.edu
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D000818:Animals; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009130:Muscle, Smooth / Q000201:enzymology / Q000502:physiology*; D009218:Myosins / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D010749:Phosphoprotein Phosphatases; D019204:GTP-Binding Proteins; D009218:Myosins