Modulation of Ca2+ Sensitivity by Agonists in Smooth Muscle

Abstract

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).