Molecular basis for cardiac muscle diseases caused by functional abnormalities of Z-disc

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In this study, we investigated functional role of Z-disc in the molecular pathogenesis of cardiomyopathy and arrhythmia to develop a novel strategy for the diseases via modifying the Z-disc function. It was deciphered that mutations in ZASP caused cardiomyopathy accompanied by ventricular arrhythmia via impairing the function of INa through affecting expression of cardiac sodium channel Nav1.5. In addition, we revealed that the mutations in SLMAP gene encoding for a Z-disc protein of unknown function. It was found that SLMAP mutations impaired INa function via inhibiting intracellular trafficking of Nav1.5. Moreover, we also revealed that a SCN3B mutation inhibited intracellular trafficking of Nav1.5 and affected INa function. These observations have indicated that the intracellular trafficking of Nav1.5 is in part controlled by Z-disc elements. On the other hand, we found that a heart-specific small subunit of myosin phosphatase, M21, localized at Z-disc and increased the phosphorylation of a large subunit of myosin phosphatase, M110, which resulted in increased calcium sensitivity of cardiac muscle contraction. Inhibition of binding between M21 and M110 suppressed the phosphorylation of M110. M21 also bound to a Rho-kinase and enhanced its kinase activity, suggesting that inhibition of rho-kinase would be useful in modulation of calcium sensitivity of cardiac muscle contraction.