Regulation of the Cardiac Sodium Channel by SIRTUIN1

描述（由申请人提供）：心脏Na+通道SCN 5A（Nav1.5）和内向去极化Na+电流（INa）在调节心房、心室和专门传导系统中的肌细胞动作电位方面发挥关键作用。SCN 5A突变与几种心律失常表型相关，包括长QT综合征、Brugada综合征和扩张型心肌病。Brugada综合征还与甘油-3-磷酸脱氢酶样（GPD 1-L）蛋白基因突变有关，该蛋白依赖于细胞NADH和NAD+的平衡，从而依赖于细胞的能量状态。SIRT 1是哺乳动物蛋白质赖氨酸脱乙酰酶，其属于NAD+依赖性脱乙酰酶的SIRTUIN家族。SIRT 1靶向许多蛋白质进行赖氨酸脱乙酰化，以响应细胞能量状态的变化。SIRT 1是否靶向心脏离子通道，特别是SCN 5A，从而在调节心脏兴奋性中发挥作用尚不清楚。此外，GPD 1-L、心室肌细胞的代谢状态和SIRT 1活性之间的潜在相互作用完全未被探索。这项修订后的申请是基于非常新颖的初步数据，即SIRT 1与Nav1.5和GPD 1-L相互作用以调节INa。它假设动态赖氨酸乙酰化和脱乙酰化是一种先前未描述的SCN 5A翻译后修饰，可调节INa，Nav1.5的SIRT 1依赖性脱乙酰化增加INa，GPD 1-L突变通过SIRT介导的Nav1.5脱乙酰化的变化改变INa，SIRT 1的变化可改变帕金森病风险。它将使用HEK 293细胞、大鼠新生心肌细胞、iPS衍生的心肌细胞和转基因小鼠来严格检验这些假设。SIRT 1介导的Nav1.5去乙酰化激活及其GPD 1-L的调节将确定一种全新的心脏INa调节机制。在这样做的过程中，它将打开大门，药理学SIRT 1激活剂作为潜在的治疗药物，在患者的心脏心律失常的风险，由于遗传性和获得性干扰心脏INa。

DESCRIPTION (provided by applicant): The cardiac Na+ channel SCN5A (Nav1.5) and the inward depolarizing Na+ current (INa) play a critical role in regulating the action potential of myocytes in the atrium, ventricle, and specialized conduction system. Mutations in SCN5A are associated with several arrhythmia phenotypes including long QT syndrome, Brugada syndrome, and dilated cardiomyopathy. Brugada Syndrome has also been linked to a mutation in the gene for the glycerol-3-phosphate dehydrogenase-like (GPD1-L) protein, which is dependent on the balance of cellular NADH and NAD+, and thus the energetic state of the cell. SIRT1 is a mammalian protein lysine deacetylase which belongs to the SIRTUIN family of NAD+-dependent deacetylases. SIRT1 targets many proteins for lysine deacetylation in response to changes in the energetic state of the cell. Whether SIRT1 targets cardiac ion channels, and SCN5A in particular, and thus plays a role in regulating cardiac excitability is not known. Moreover, potential interactions between GPD1-L, the metabolic state of ventricular myocytes, and SIRT1 activity are completely unexplored. This revised application is based on very novel preliminary data that SIRT1 interacts with Nav1.5 and GPD1-L to regulate INa. It hypothesizes that dynamic lysine acetylation and deacetylation is a previously undescribed post-translational modification of SCN5A that regulates INa, that SIRT1-dependent deacetylation of Nav1.5 increases INa, that GPD1-L mutations alter INa through changes in SIRT-mediated deacetylation of Nav1.5, and that changes in SIRT1 can modify arrhythmic risk. It will critically test these hypotheses using HEK 293 cells, rat neonatal cardiac myocytes, iPS-derived cardiac myocytes and transgenic mice. Deacetylation-mediated activation of Nav1.5 by SIRT1, and its modulation by GPD1-L, will identify an entirely new mechanism for regulation of cardiac INa. In doing so, it will open the door for pharmacologic SIRT1 activators as potential therapeutic agents in patients at risk for cardiac arrhythmias dues to inherited and acquired disturbances in cardiac INa.