From pharmacomechanical coupling to G-proteins and myosin phosphatase.
A brief summary of recent studies of pharmacomechanical coupling is presented, with emphasis on the role of GTP-binding proteins and Ca(2+)-independent regulation of contraction (Ca(2+)-sensitization/desensitization) through regulatory myosin light chain (MLC20) phosphorylation and dephosphorylation. Pharmacomechanical regulation of cytosolic [Ca2+] is largely, though not solely, controlled by the phosphatidylinositol cascade and Ca(2+)-pumps of the plasma membrane and the sarcoplasmic reticulum. The monomeric GTPase, RhoA, is a major upstream component of Ca(2+)-sensitization. Its crystal structure and apparently obligatory translocation to the plasma membrane for activation of its downstream effectors are described. Inhibition of RhoA activity by a membrane-permeant ADP-ribosylating bacterial exoenzyme, DC3B, causes severe depression of the tonic component of agonist-induced contraction, suggesting that this component is largely due to Ca(2+)-sensitization. A relatively specific inhibitor (Y27632) of Rho-kinase, a downstream effector of Ca(2+)-sensitization (Uehata et al 1997), also inhibits oxytoxin-induced Ca(2+)-sensitization of myometrium. The major mechanism of physiological, G-protein-coupled Ca(2+)-sensitization is through inhibition of smooth muscle myosin phosphatase (SMPP-1M), whereas conventional or novel protein kinase Cs play very little or no role in this process. Mechanisms of Ca(2+)-desensitization include inhibition of myosin light chain kinase and activation of SMPP-1M. Activation of SMPP-1M in phasic smooth muscle can be attributed, at least in part, to the synergistic phosphatase activating activities of a cyclic nucleotide-dependent kinase and its major substrate, telokin.
Somlyo
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AP
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville 22906-0011, USA.
Somlyo
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AV
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D009219:Myosin-Light-Chain Kinase / Q000502:physiology; D043263:Myosin-Light-Chain Phosphatase; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*
D009219:Myosin-Light-Chain Kinase; D010749:Phosphoprotein Phosphatases; D043263:Myosin-Light-Chain Phosphatase; D019204:GTP-Binding Proteins