Moreau Adrien, Gosselin-Badaroudine Pascal, Boutjdir Mohamed, Chahine Mohamed
Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec City QC, Canada.
Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn NY, USA.
Front Pharmacol. 2015 Dec 24;6:301. doi: 10.3389/fphar.2015.00301. eCollection 2015.
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.
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）的突变与心律失常合并扩张型心肌病的发生有关。已观察到与三种不相关的突变相关的门控孔电流，这些突变具有相似的临床表型。然而，门控孔从未与Nav1.5第一个结构域以外的突变相关联。本研究的目的是探讨门控孔电流可能由Nav1.5 R225P和R814W突变（分别位于结构域I和结构域II的R3、S4）引起的可能性，这两种突变与节律紊乱和扩张型心肌病有关。Nav1.5野生型和突变型通道在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以及门控孔电流的存在情况。我们证实了先前报道的突变型通道α孔功能增强，主要表现为窗口电流增加，这主要是由激活电压依赖性的改变引起的。我们还观察到与R225P和R814W突变相关的门控孔电流。这种新的通透途径在去极化条件下开放，在去极化期后超极化电位时仍会暂时开放。门控孔电流可能是罕见电异常和心脏形态改变发生的分子基础。我们建议在VSD上发生Nav1.5突变的情况下常规评估这种生物物理缺陷。
