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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Signaling for contraction and relaxation in smooth muscle of the gut.

Phosphorylation of Ser(19) on the 20-kDa regulatory light chain of myosin II (MLC(20)) by Ca(2+)/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca(2+)](i) transient is rapidly dissipated and MLCK inactivated, whereas MLC(20) and muscle contraction are well maintained. Sustained contraction does not reflect Ca(2+) sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca(2+) induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca(2+)-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca(2+) concentrations, involves (a) G protein activation, (b) regulated inhibition of MLC phosphatase, and (c) MLC(20) phosphorylation via a Ca(2+)-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by G(q/13)-coupled receptors are initiated by sequential activation of Galpha(q)/alpha(13), 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(20) phosphorylation is probably induced by the Ca(2+)-independent MLCK, ZIP kinase. The pathways initiated by G(i)-coupled receptors involve sequential activation of Gbetagamma(i), PI 3-kinase, and the Ca(2+)-independent MLCK, integrin-linked kinase. The last phosphorylates MLC(20) directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC(2) 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 (a) initial contraction by inhibiting Ca(2+) mobilization and (b) sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC(20) dephosphorylation and muscle relaxation.[1]


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