Regulation of Cardiac Voltage-Gated Sodium Channel by Kinases: Roles of Protein Kinases A and C
Regulation of Cardiac Voltage-Gated Sodium Channel by Kinases: Roles of Protein Kinases A and C
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DOI：
10.1007/164_2017_53
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Boutjdir, Mohamed
中科院分区：
文献类型：
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作者：
Aromolaran, Ademuyiwa S.;Chahine, Mohamed;Boutjdir, Mohamed
在心脏中，电压门控钠(Na(V))通道(Na(V)1.5)由其成孔的a亚基和辅助的β亚基组成，这两个亚基对启动和维持构成正常心律的心脏动作电位(AP)具有重要作用。Na(V)1.5通道基因SCN5A的遗传或先天突变导致功能表达的改变(包括表达、转运和电流密度)，通常表现为不同的心律失常事件、癫痫、神经病理性疼痛、偏头痛和神经肌肉疾病，这一事实进一步证明了Na(V)1.5的生理学相关性。然而，尽管在定义Na(V)1.5的病理生理学方面取得了重大进展，但其调控和对心脏疾病的贡献的分子机制却知之甚少。越来越明显的是，Na(V)1.5的功能表达(定位、运输和门控)可能受到与磷酸化相关的翻译后修饰的调节。我们在此综述了蛋白激酶(PKA和PKC)调节心肌钠通道的分子基础及其功能后果。具体地说，我们讨论了：(1)关于心脏Na(V)1.5通道的结构、分子和功能特性的最新文献；(2)由于Na(V)1.5通道和/或亚单位的先天性突变，如长QT和Brugada综合征，这些特性如何在疾病状态下被磷酸化改变。我们的期望是，了解这些不同和复杂的磷酸化过程在Na(V)1.5功能表达中的作用可能会为Na通道相关的心律失常事件提供关键的机制见解，并将有助于开发新的治疗策略。
In the heart, voltage-gated sodium (Na-v) channel (Na(v)1.5) is defined by its pore-forming a-subunit and its auxiliary beta-subunits, both of which are important for its critical contribution to the initiation and maintenance of the cardiac action potential (AP) that underlie normal heart rhythm. The physiological relevance of Na(v)1.5 is further marked by the fact that inherited or congenital mutations in Na(v)1.5 channel gene SCN5A lead to altered functional expression (including expression, trafficking, and current density), and are generally manifested in the form of distinct cardiac arrhythmic events, epilepsy, neuropathic pain, migraine, and neuromuscular disorders. However, despite significant advances in defining the pathophysiology of Na(v)1.5, the molecular mechanisms that underlie its regulation and contribution to cardiac disorders are poorly understood. It is rapidly becoming evident that the functional expression (localization, trafficking and gating) of Na(v)1.5 may be under modulation by post-translational modifications that are associated with phosphorylation. We review here the molecular basis of cardiac Na channel regulation by kinases (PKA and PKC) and the resulting functional consequences. Specifically, we discuss: (1) recent literature on the structural, molecular, and functional properties of cardiac Na(v)1.5 channels; (2) how these properties may be altered by phosphorylation in disease states underlain by congenital mutations in Na(v)1.5 channel and/ or subunits such as long QT and Brugada syndromes. Our expectation is that understanding the roles of these distinct and complex phosphorylation processes on the functional expression of Na(v)1.5 is likely to provide crucial mechanistic insights into Na channel associated arrhythmogenic events and will facilitate the development of novel therapeutic strategies.