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

在本研究中，我们研究了Z-Disc在心肌病和心律失常分子发病机制中的功能作用，以期通过改变Z-Disc的功能来开发一种新的治疗这些疾病的策略。已有研究表明，ZASP基因突变通过影响心肌钠通道NaV1.5的表达而损害INA的功能，从而导致心肌病并发室性心律失常。此外，我们还发现了编码未知功能的Z-Disc蛋白的SLMAP基因突变。研究发现，SLMAP突变通过抑制NaV1.5的细胞内转运而损害Ina的功能。此外，我们还发现SCN3B突变抑制了NaV1.5在细胞内的转运，并影响了Ina的功能。这些观察结果表明，NaV1.5的细胞内转运部分受Z-Disc元件控制。另一方面，我们发现心脏特异的肌球蛋白磷酸酶小亚基M21定位于Z-Disc，并增加了肌球蛋白磷酸酶大亚基M110的磷酸化，从而导致心肌收缩对钙的敏感性增加。抑制M21与M110的结合抑制了M110的磷酸化。M21还与Rho-Kinase结合并增强其活性，提示抑制Rho-Kinase可能有助于调节心肌收缩的钙敏感性。

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.