Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañón, and CIBER of Cardiovascular Diseases, Madrid, Spain.
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Universidad Autónoma de Madrid, Madrid, Spain.
JCI Insight. 2018 Sep 20;3(18). doi: 10.1172/jci.insight.96291.
Cardiac Nav1.5 and Kir2.1-2.3 channels generate Na (INa) and inward rectifier K (IK1) currents, respectively. The functional INa and IK1 interplay is reinforced by the positive and reciprocal modulation between Nav15 and Kir2.1/2.2 channels to strengthen the control of ventricular excitability. Loss-of-function mutations in the SCN5A gene, which encodes Nav1.5 channels, underlie several inherited arrhythmogenic syndromes, including Brugada syndrome (BrS). We investigated whether the presence of BrS-associated mutations alters IK1 density concomitantly with INa density. Results obtained using mouse models of SCN5A haploinsufficiency, and the overexpression of native and mutated Nav1.5 channels in expression systems - rat ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) - demonstrated that endoplasmic reticulum (ER) trafficking-defective Nav1.5 channels significantly decreased IK1, since they did not positively modulate Kir2.1/2.2 channels. Moreover, Golgi trafficking-defective Nav1.5 mutants produced a dominant negative effect on Kir2.1/2.2 and thus an additional IK1 reduction. Moreover, ER trafficking-defective Nav1.5 channels can be partially rescued by Kir2.1/2.2 channels through an unconventional secretory route that involves Golgi reassembly stacking proteins (GRASPs). Therefore, cardiac excitability would be greatly affected in subjects harboring Nav1.5 mutations with Golgi trafficking defects, since these mutants can concomitantly trap Kir2.1/2.2 channels, thus unexpectedly decreasing IK1 in addition to INa.
心脏钠离子通道 Nav1.5 和内向整流钾通道 Kir2.1-2.3 分别产生钠电流 (INa) 和内向整流钾电流 (IK1)。Nav15 与 Kir2.1/2.2 通道之间的正向和相互调节加强了功能性 INa 和 IK1 的相互作用，从而增强了对心室兴奋性的控制。编码 Nav1.5 通道的 SCN5A 基因突变是几种遗传性心律失常综合征（包括 Brugada 综合征，BrS）的基础。我们研究了 BrS 相关突变是否会同时改变 IK1 密度和 INa 密度。通过 SCN5A 杂合子不足的小鼠模型、表达系统中天然和突变 Nav1.5 通道的过表达（大鼠心室肌细胞和人诱导多能干细胞衍生的心肌细胞，hiPSC-CMs）获得的结果表明，内质网（ER）转运缺陷型 Nav1.5 通道显著降低了 IK1，因为它们没有正向调节 Kir2.1/2.2 通道。此外，高尔基体转运缺陷型 Nav1.5 突变体对 Kir2.1/2.2 产生显性负效应，从而导致 IK1 进一步减少。此外，ER 转运缺陷型 Nav1.5 通道可以通过涉及高尔基体重组堆叠蛋白（GRASPs）的非常规分泌途径，部分被 Kir2.1/2.2 通道挽救。因此，在存在高尔基体转运缺陷型 Nav1.5 突变的个体中，心脏兴奋性会受到极大影响，因为这些突变体可以同时捕获 Kir2.1/2.2 通道，从而意外地除了 INa 之外还降低了 IK1。
