The cardiac sodium channel Na_V1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some Na_V1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective Na_V1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the Na_V1.5 complex. In this alternative view, alterations in Na_V1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of Na_V1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through Na_V1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of Na_V1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of Na_V1.5 is essential for the development of novel preventive and therapeutic strategies.

中文翻译：

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与异常心脏钠通道功能相关的遗传性心律失常综合征：离子和非离子机制。

由SCN5A基因编码的心脏钠通道 Na _V 1.5负责动作电位的快速上升。SCN5A突变可能通过降低峰值钠电流导致钠通道功能障碍，这会减慢传导并促进折返性心律失常，并通过增强晚期钠电流，从而延长动作电位并为早期后去极化和心律失常奠定基础。然而，一些 Na _V 1.5 相关疾病，特别是结构异常，不能直接或完全基于 Na _V 1.5 表达或生物物理学缺陷来解释。一个新兴概念可以解释与SCN5A相关的大疾病谱突变以 Na _V 1.5 复合物的多功能性为中心。在这个替代观点中，Na _V 1.5 的改变会影响独立于其规范离子传导作用的过程。我们在这里提出了 Na _V 1.5（功能障碍）功能的新分类，分为（i）钠通过 Na _V 1.5流入对膜电位和随后的动作电位产生的直接离子效应，（ii）钠流入对细胞内的间接离子效应稳态和信号传导，以及 (iii) Na _{V 的}非离子效应1.5，独立于钠流入，通过与心肌细胞不同微域内的大分子复合物相互作用。这些间接的离子和非离子过程可能单独或协同作用显着促进心律失常的发生。因此，进一步探索 Na _V 1.5的这些多功能作用对于开发新的预防和治疗策略至关重要。