Novel molecular mechanisms for cardiotonic action, their involvement in diseases and application for treatment

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The regulatory mechanism, function and the involvement in pathologic conditions of cardiac myosin light chain (MLC2) phosphorylation were investigated. Cardiac MLC2 was found to be phosphorylated by cardiac myosin light chain kinase (cMLCK), but not by smooth MLCK nor ZIP-kinase. However, cMLCK was not detected in several animal species, suggesting the existence of another (iso)forms of cardiac MLCK. Biochemical characteristics of cMLCK were different from those of smMLCK including the enzyme kinetics and the sensitivity for antagonists. The overexpression of cardiac myosin phosphatase in heart induced a reduction of MLC2 phosphorylation levels concomitant with a Ca^<2+> desensitization of contraction and decreased LV contractility, resulting in LV enlargement. Thus the phosphorylation of cardiac MLC2 plays a significant role in maintaining normal cardiac function. Agonist stimulation including endothelin-1 induced the expression of cMLCK and increased the phosphorylation level of MLC2. In addition, the expression of cMLCK and the phosphorylation levels of MLC2 were varied in several animal models, suggesting the phosphorylation of MLC2 might be involved in the several pathologic conditions in heart.