ACTIN-BASED REGULATION OF SMOOTH MUSCLE CONTRACTION

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The contraction of skeletal, cardiac and smooth muscles occurs by an ATP dependent interaction of the proteins myosin and actin. These same proteins are also required for several critical processes, such as cell division, in nonmuscle cells. The force producing interaction between actin and myosin is regulated by changes in either myosin or actin. Whereas skeletal and cardiac muscle are regulated primarily through the actin filament, by the proteins tropomyosin and troponin, smooth muscle has been thought to be regulated by the level of phosphorylation of myosin. Evidence from several laboratories suggest that smooth muscle contraction may also be modulated by actin binding proteins. Two proteins implicated in this activity are caldesmon and calponin. Both proteins are known to inhibit the high rate of ATP hydrolysis that occurs in the presence of both myosin and actin. We hope to determine the mechanism by which these proteins function and make particular note of differences with the tropomyosin-troponin system of skeletal and cardiac muscle. This will be done by determining the effect of these proteins, individually and in combination, on the binding of various chemical states of myosin to actin. We will also use stopped flow kinetic measurements to determine the effect of these proteins on key transitions between actomyosin states. We also hope to demonstrate the function of these proteins in smooth muscle cells. Differences in regulation from skeletal and cardiac muscle may be exploited for the intervention of hypertension, uterine disorders, digestive disorders or other disorders involving smooth muscle contraction.