Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam UMC (location AMC), University of Amsterdam, Amsterdam Cardiovascular Sciences, Meigberdreef 15, 1105AZ Amsterdam, The Netherlands.
The Leon H. Charney Division of Cardiology, New York University School of Medicine, 435 E 30th St, NSB 707, New York, NY 10016, USA.
Cardiovasc Res. 2020 Jul 15;116(9):1557-1570. doi: 10.1093/cvr/cvaa082.
The cardiac sodium channel NaV1.5, 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 NaV1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective NaV1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the NaV1.5 complex. In this alternative view, alterations in NaV1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of NaV1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through NaV1.5 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 NaV1.5, 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 NaV1.5 is essential for the development of novel preventive and therapeutic strategies.
心脏钠离子通道 NaV1.5 由 SCN5A 基因编码，负责动作电位的快速上升。SCN5A 突变可通过减少峰值钠离子电流导致钠离子通道功能障碍，从而减慢传导并促进折返性心律失常，通过增强晚期钠离子电流延长动作电位并为早期后除极和心律失常奠定基础。然而，一些与 NaV1.5 相关的疾病，特别是结构性异常，不能直接或仅基于 NaV1.5 表达或生物物理学的缺陷来解释。一种新的概念可能解释与 SCN5A 突变相关的广泛疾病谱，其中心围绕着 NaV1.5 复合物的多功能性。在这种替代观点中，NaV1.5 的改变会影响与其经典离子传导作用无关的过程。在这里，我们提出了一种新的 NaV1.5（功能障碍）分类方法，分为 (i) 通过 NaV1.5 钠离子内流对膜电位和随后的动作电位产生的直接离子效应，(ii) 钠离子内流对细胞内稳态和信号转导的间接离子效应，以及 (iii) NaV1.5 的非离子效应，与钠离子内流无关，通过与心肌细胞不同微区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，对心律失常的发生有重要贡献。因此，进一步探索 NaV1.5 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。
