Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia
Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia
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DOI：
10.1161/circresaha.107.164673
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发表时间：
2008-02-15
影响因子：
20.1
通讯作者：
George, Alfred L., Jr.
中科院分区：
文献类型：
--
作者：
Nguyen, Thao P.;Wang, Dao W.;George, Alfred L., Jr.
编码人心脏中表达的主要Na+通道α-亚基（Na（V）1.5）的SCN 5A突变最近与具有房性和室性心律失常的扩张型心肌病的遗传形式有关。我们使用培养的tsA 201细胞中的异源表达和全细胞膜片钳记录，比较了与该综合征相关的2种新型NaV1.5突变（D2/S4 -R814 W; D4/S3 -D1595 H）与野生型（WT）通道的生物物理特性。WT和突变体通道之间的表达水平相似，并且两种突变都不影响持续钠电流。R814 W通道在激活的动力学和电压依赖性方面表现出突出和新颖的缺陷，其特征在于较慢的上升时间和超极化电导-电压关系，导致“窗口电流”增加。“这种突变体还显示出增强的缓慢失活和更大的使用依赖性降低峰值电流在快速脉冲频率。相比之下，D1595 H通道表现出受损的快速失活，其特征在于进入失活状态和超极化稳态失活曲线较慢。我们的研究结果说明了与家族性扩张型心肌病相关的2种不同的SCN 5A突变引起的不同的生物物理缺陷。对已发表临床数据的回顾性审查表明，心肌病在D1595 H家族中并不常见，而窦性心动过缓是主要的临床发现。然而，对于R814 W，我们推测，增加的窗口电流加上增强的缓慢失活和通道可用性的速率依赖性损失提供了一个独特的基板诱发心肌细胞的Na+和Ca 2+稳态紊乱，导致心肌功能障碍。
Mutations in SCN5A encoding the principal Na+ channel alpha-subunit expressed in human heart (Na(V)1.5) have recently been linked to an inherited form of dilated cardiomyopathy with atrial and ventricular arrhythmia. We compared the biophysical properties of 2 novel NaV1.5 mutations associated with this syndrome (D2/S4 - R814W; D4/S3 - D1595H) with the wild-type (WT) channel using heterologous expression in cultured tsA201 cells and whole-cell patch-clamp recording. Expression levels were similar among WT and mutant channels, and neither mutation affected persistent sodium current. R814W channels exhibited prominent and novel defects in the kinetics and voltage dependence of activation characterized by slower rise times and a hyperpolarized conductance-voltage relationship resulting in an increased "window current." This mutant also displayed enhanced slow inactivation and greater use-dependent reduction in peak current at fast pulsing frequencies. By contrast, D1595H channels exhibited impaired fast inactivation characterized by slower entry into the inactivated state and a hyperpolarized steady-state inactivation curve. Our findings illustrate the divergent biophysical defects caused by 2 different SCN5A mutations associated with familial dilated cardiomyopathy. Retrospective review of the published clinical data suggested that cardiomyopathy was not common in the family with D1595H, but rather sinus bradycardia was the predominant clinical finding. However, for R814W, we speculate that an increased window current coupled with enhanced slow inactivation and rate-dependent loss of channel availability provided a unique substrate predisposing myocytes to disordered Na+ and Ca2+ homeostasis leading to myocardial dysfunction.