Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease.
Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease.
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DOI：
10.1161/circulationaha.112.105320
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发表时间：
2012-10-23
期刊：
影响因子：
37.8
通讯作者：
Hund TJ
中科院分区：
文献类型：
--
作者：
Koval OM;Snyder JS;Wolf RM;Pavlovicz RE;Glynn P;Curran J;Leymaster ND;Dun W;Wright PJ;Cardona N;Qian L;Mitchell CC;Boyden PA;Binkley PF;Li C;Anderson ME;Mohler PJ;Hund TJ
影响离子通道生物物理活性和/或膜定位的人类基因变异与潜在的致命性心律失常有关。然而，尽管经过十多年的研究，许多人类心律失常变体的机制仍不明确。膜蛋白的翻译后调节对于正常的心脏功能是必不可少的。重要的是，异常的肌细胞信号传导与心脏离子通道翻译后修饰缺陷和疾病有关。我们最近发现了一种新的途径，主要心脏电压门控Na+通道（Nav1.5）的翻译后调节CaMK Ⅱ。然而，这一途径在心脏病中的作用尚未得到评估。我们评估了CaMKII依赖性磷酸化在人类遗传和获得性疾病中的作用。我们报告了Nav1.5 DI-DII环中的一个短基序与Nav1.5在单基因心律失常和常见心脏病中的功能之间的意外联系，该基序最近被证明对CaMKII依赖性磷酸化至关重要。在异源细胞和原代心室心肌细胞中的实验表明，人类心律失常易感性变体（A572 D和Q573 E）改变Nav1.5的CaMK II依赖性调节，导致异常通道活性和细胞兴奋性。计算机模拟分析表明，这些变体在功能上模拟磷酸化通道，从而增加了对帕金森病触发后去极化的易感性。最后，我们报告说，这个相同的主题是异常调节的大型动物模型获得性心脏病和失败的人类心肌。我们确定了两种人类心律失常变体的机制，这些变体通过直接影响通道翻译后修饰来影响Nav1.5通道活性。我们认为Nav1.5 DI-DII胞质环中的CaMKII磷酸化基序是先天性和获得性心脏病中Nav1.5促凋亡变化的关键节点。
Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked with potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite over a decade of investigation. Post-translational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel post-translational modifications and disease. We recently identified a novel pathway for post-translational regulation of the primary cardiac voltage-gated Na+ channel (Nav1.5) by CaMKII. However, a role for this pathway in cardiac disease has not been evaluated. We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Nav1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Nav1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Nav1.5 resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large animal model of acquired heart disease and in failing human myocardium. We identify the mechanism for two human arrhythmia variants that affect Nav1.5 channel activity through direct effects on channel post-translational modification. We propose that the CaMKII phosphorylation motif in the Nav1.5 DI-DII cytoplasmic loop is a critical nodal point for pro-arrhythmic changes to Nav1.5 in congenital and acquired cardiac disease.