Sodium channels and the intercalated disk - it is all about location, location, location.
Sodium channels and the intercalated disk - it is all about location, location, location.
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DOI：
10.1113/jp282350
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Weinberg SH
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文献类型：
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作者：
Veeraraghavan R;Moise N;Weinberg SH
心律失常通常由电脉冲传导缺陷驱动，并且常见于多种病理，包括心力衰竭和心肌病。然而，心律失常的结构基础已被证明难以在实验环境中研究或影响，在临床中更是如此。新出现的证据表明，心律失常的结构基板可以存在于亚细胞空间尺度延伸到纳米水平。这些证据主要来自于对细胞间接触位点闰盘（ID）的实验和建模研究。ID是间隙连接（GJ）和心脏电压门控Na+通道（NaV1. 5），其被认为是心脏组织中的电传导的关键决定因素。已知GJ和Na+通道蛋白在称为perinexi的狭窄膜间分离区域内聚集并形成纳米结构域。perinexi和ID的破坏与心律失常的风险增加相关：ID纳米结构域的实验扰动诱导promammic传导缺陷，并且已经在人类心律失常患者中鉴定出perinexal纳米结构域的破坏。1然而，现有技术的局限性妨碍了在纳米尺度上对心脏脉冲传播进行直接的功能研究。因此，在可预见的未来，计算模型将是唯一能够解决这些问题的方法。虽然传统的心脏组织建模方法通常忽略ID结构和Na+通道聚类，因此无法表示这些ID扰动，但早期的研究已经建模了ID的简化表示。Kucera等人确定了一个关键机制，其中Na+通道位于ID影响传导：ID本地化的Na+电流超极化的细胞间隙（耦合的肌细胞之间的狭窄的细胞外空间），极化后连接ID膜和激活下游Na+电流。[2]这些发生在细胞外空间的相互作用统称为肝纤维化偶联。该研究和其他研究表明，肝纤维化耦合可以以复杂的方式影响传导，这取决于结构和组织特性，包括GJ耦合、裂隙宽度和ID Na+通道定位。3
Cardiac arrhythmias are often driven by defects in electrical impulse conduction and are common to multiple pathologies, including heart failure and cardiomyopathy. However, the structural substrate of arrhythmias has proven difficult to study or influence in an experimental setting, and even more so in the clinic. Emerging evidence suggests that structural substrates for arrhythmias can exist at subcellular spatial scales extending down to the nanometer level. Such evidence derives mainly from experimental and modeling studies of the intercalated disk (ID), sites of cell-cell contact. The ID is home to gap junctions (GJ) and cardiac voltage-gated Na+ channels (NaV1. 5), which are considered to be critical determinants of electrical conduction in cardiac tissue. The GJ and Na+ channel proteins are known to cluster and form nanodomains within regions of narrow intermembrane separation called the perinexi. Disruption of perinexi and the ID is associated with increased risk for arrhythmias: experimental perturbation of ID nanodomains induces proarrhythmic conduction defects, and disruption of perinexal nanodomains has been identified in human arrhythmia patients. 1 However, limitations of current technology preclude direct functional investigation of cardiac impulse propagation at the nanoscale. Thus, for the foreseeable future, computational models will be uniquely capable of tackling such questions.While conventional cardiac tissue modeling approaches typically neglect ID structure and Na+ channel clustering, and therefore cannot represent these ID perturbations, earlier studies have modeled simplified representations of the ID. Kucera et al identified a critical mechanism in which Na+ channels localized at the ID impact conduction: ID-localized Na+ currents hyperpolarized the intercellular cleft (the narrow extracellular space between coupled myocytes), which polarized the post-junctional ID membrane and activated downstream Na+ current. 2 These interactions occurring in the extracellular space are collectively termed ephaptic coupling. This and other studies showed that ephaptic coupling can impact conduction in a complex manner, dependent on structural and tissue properties including GJ coupling, cleft width, and ID Na+ channel localization. 3