From pharmacomechanical coupling to G‐proteins and myosin phosphatase

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Abstract
A brief summary of recent studies of pharmacomechanical coupling is presented, with emphasis on the role of GTP‐binding proteins and Ca2+‐independent regulation of contraction (Ca2+‐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 Ca2+‐pumps of the plasma membrane and the sarcoplasmic reticulum. The monomeric GTPase, RhoA, is a major upstream component of Ca2+‐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 Ca2+‐sensitization. A relatively specific inhibitor (Y27632) of Rho‐kinase, a downstream effector of Ca2+‐sensitization (Uehata et al 1997), also inhibits oxytocin‐induced Ca2+‐sensitization of myometrium. The major mechanism of physiological, G‐protein‐coupled Ca2+‐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 Ca2+‐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.