Modulation of Ca2+ Sensitivity by Agonists in Smooth Muscle
The fact that Ca2+ is the primary physiological regulator of smooth muscle contraction is no longer questioned. Cytoplasmic Ca2+ can be increased through electromechanical coupling and through pharmacomechanical coupling (Somlyo and Somlyo, 1968). The two components of pharmacomechanical coupling explored, until recently, are ligand-gated Ca2+ influx and G-protein coupled activation of the phosphatidylinositol cascade that results in inositol 1,4,5-trisphosphate (InsP3) -induced Ca2+-release. However, several lines of evidence suggest that cytoplasmic Ca2+ concentration and force are not rigidly coupled and the Ca2+-sensitivity of the regulatory/contractile apparatus can be modified by physiological mechanisms. The force/Ca2+ ratio in intact smooth muscles studied with Ca2+-indicators is higher during agonist- than during high K+-induced contractions (Bradley and Morgan, 1987; Himpens and Casteels, 1987; Rembold and Murphy 1988; Sato et al., 1988; Himpens et al., 1990). Recently, this agonist-induced increase in Ca2+-sensitivity was unequivocally demonstrated in preparations permeabilized with Staphylococcus aureus α-toxin (Nishimura et al., 1988; Kitazawa et al., 1989) or with β-escin (Kobayashi et al., 1989) that retain agonist-coupled responses. Various agonists can markedly increase the contractile response of such preparations to a fixed, submaximal level of Ca2+. Therefore, we had suggested that the third excitatory component of pharmacomechanical coupling (Somlyo and Somlyo, 1968), modulation of Ca2+-sensitivity, operates by increasing myosin light chain (MLC) phosphorylation at a given level of cytoplasmic Ca2+ (Somlyo et al., 1989). In the following, we shall summarize our recent data (Kitazawa and Somlyo, 1990; Kitazawa et al., 1991) on the mechanism of the agonist-induced increase in Ca2+-sensitivity of force associated with increased phosphorylation of MLC. In addition, we will show that phasic contractile responses of ileum smooth muscle are due, at least in part, to a time and/or Ca2+-dependent desensitization of MLC phosphorylation (Kitazawa and Somlyo, 1990). The other two components of pharmacomechanical coupling have been described elsewhere (see Somlyo et al. this volume).
KeywordsSmooth Muscle Portal Vein Contractile Response Myosin Light Chain Phosphorylation Rabbit Pulmonary Artery
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