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).