Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents.
Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents.
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DOI：
10.3389/fphar.2015.00301
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发表时间：
2015
影响因子：
5.6
通讯作者：
Chahine M
中科院分区：
文献类型：
--
作者：
Moreau A;Gosselin-Badaroudine P;Boutjdir M;Chahine M
电压门控钠通道（Nav）是负责动作电位起始的跨膜蛋白。主要位于心脏钠通道Nav1.5的电压传感器结构域（VSD）的突变与扩张型心肌病合并心律失常的发生有关。门控孔电流已被观察到与三个无关的突变与相似的临床表型。然而，门控孔从未与Nav1.5第一结构域以外的突变相关。本研究的目的是探索门控孔电流可能由Nav1.5 R225 P和R814 W突变（分别为DI和DII中的R3、S4）引起的可能性，这些突变与心律失常和扩张性心肌病相关。Nav1.5 WT和突变体通道在tsA201细胞中瞬时表达。使用膜片钳技术研究了α孔电流的生物物理特性和门控孔电流的存在。我们证实了先前报道的突变体通道的α孔功能的增益，其主要包括主要由激活的电压依赖性的偏移引起的增加的窗口电流。我们还观察到与R225 P和R814 W突变相关的门控孔电流。这种新的渗透途径在去极化条件下是开放的，并且在去极化期后在超极化电位下保持暂时开放。门控孔电流可能代表了不常见的电异常和心脏形态学变化的发展的分子基础。我们建议在VSD上Nav1.5突变的情况下常规评估这种生物物理缺陷。
Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5. The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy. Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique. We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods. Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD.