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Acta Physiol Scand. 1998 Dec;164(4):437-48.

From pharmacomechanical coupling to G-proteins and myosin phosphatase.

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  • 1Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville 22906-0011, USA.

Erratum in

  • Acta Physiol Scand 1999 Apr;165(4):423.

Abstract

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.

PMID:
9887967
[PubMed - indexed for MEDLINE]
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