Dual Regulation of Smooth Muscle Contraction

Abstract

Smooth muscle contraction is initiated by an increase in cytosolic Ca2+. Ca2+, together with calmodulin, activates myosin light chain kinase to phosphorylate myosin light chain. Phosphorylated myosin interacts with actin to form cycling cross-bridges and generates force. During maintained force, however, the amount of phosphorylated myosin gradually decreases, suggesting that not only phosphorylated myosin but also unphosphorylated myosin is involved in cross-bridge cycling. A latch model and the positive cooperativity model suggest that formation of unphosphorylated cycling cross-bridges is regulated by the amount of phosphorylated cross-bridges. In addition to the time-dependent dissociation between myosin phosphorylation and contraction, there is a different type of dissociation, a stimulus-dependent dissociation between cytosolic Ca2+ level and contraction. Part of this dissociation is explained by the agonist-induced increase in Ca2+ sensitivity of myosin phosphorylation. Our results suggest that agonists also activate the cycling of unphosphorylated cross-bridges in the absence of myosin phosphorylation or myosin light chain kinase activity. This mechanism is activated at lower Ca2+ levels than myosin light chain kinase and may play an important role in agonist-induced Ca2+ sensitization. Although the details of this mechanism are not clear, we know that it is not regulated by the activation of protein kinase C. Thus there seem to be two regulation mechanisms of smooth muscle contraction: the mechanism dependent on and the mechanism not dependent on the phosphorylation of myosin light chain.