▪ Abstract 

Phosphorylation of Ser19 on the 20-kDa regulatory light chain of myosin II (MLC) by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca2+] transient is rapidly dissipated and MLCK inactivated, whereas MLC and muscle contraction are well maintained. Sustained contraction does not reflect Ca2+ sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca2+ induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca2+-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca2+ concentrations, involves () G protein activation, () regulated inhibition of MLC phosphatase, and () MLC phosphorylation via a Ca2+-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by G-coupled receptors are initiated by sequential activation of Gα, RhoGEF, and RhoA, and involve Rho kinase–mediated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-mediated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. Sustained MLC phosphorylation is probably induced by the Ca2+-independent MLCK, ZIP kinase. The pathways initiated by G-coupled receptors involve sequential activation of Gβγ, PI 3-kinase, and the Ca2+-independent MLCK, integrin-linked kinase. The last phosphorylates MLC directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities. These kinases also act downstream to inhibit () initial contraction by inhibiting Ca2+ mobilization and () sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC dephosphorylation and muscle relaxation.


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  • Article Type: Review Article
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