Cardiac Ion Channel Regulation

描述（由申请人提供）：心脏兴奋性由去极化和复极化电流的组合精细控制。许多内向和外向离子电流的精细调节和失调被认为在许多临床相关的心律失常中起主要作用。事实上，现在已经确定，即使是由离子通道功能障碍引起的心脏动作电位特性的微小改变，也可能导致称为通道病的心脏疾病。经典形式主义教导离子通道根据它们各自的时间和电压依赖性生物物理特性彼此独立地起作用。这是为理解单细胞电生理行为而开发的计算机模型的基础。然而，在Brugada综合征（BrS）中，一种由钠通道突变引起的遗传性心律失常，介导钾（Ito）和钠（INa）电流的通道之间的功能相互作用已被认为涉及两种主要的致心律失常机制：复极障碍和传导障碍假说。因此，是否有可能调节离子通道亚单位介导的这两个主要电流的心脏动作电位是协调的？值得注意的是，我们最近的工作是第一个支持这一挑衅性的想法，去极化钠通道和复极化钾通道Ito的表达可能有一个共同的，尚未确定的，监管机制。在Ito的辅助亚基KChIP2基因沉默后，申请人发现Ito和INa的表达被消除，产生不可兴奋的心肌细胞。这表明介导这两种主要电流的离子通道的调节可以协调。这将代表关于离子通道表达和调节的范式转变概念。因此，我们推测KChIP2通过多种调节机制控制去极化（INa）和复极化（Ito）电流的表达。这项建议的具体目标是：1.识别由KChIP2调节的基因。2.确定INa和Ito的调节是否涉及microRNA。3.确定KChIP2 miRNA依赖性调节在心脏病理学中的作用。这种调节的分子基础的描绘是必不可少的心脏心室去极化和复极及其紊乱，与致命的室性心律失常的准确理解。KChIP2的进一步功能解剖将提供对心脏功能的许多方面的洞察，将阐明KChIP2蛋白家族在疾病中的作用，并可能揭示离子通道功能在健康和疾病中的新范式。

DESCRIPTION (provided by applicant): Cardiac excitability is finely controlled by a combination of depolarizing and repolarizing currents. Fine regulation and dysregulation of a host of inward and outward ion currents are thought to play a major role in numerous clinically relevant cardiac arrhythmias. In fact, it is now well established that even subtle alterations of the cardiac action potential properties caused by dysfunction of ion channels, may lead to cardiac disorders known as channelopathies. Classic formalism teaches that ion channels function independently of each other according to their individual time- and voltage- dependent biophysical properties. This is the basis for computer models developed to understand single cell electrophysiological behavior. However, in Brugada syndrome (BrS), a form of genetic arrhythmia caused by mutations in the sodium channel, functional interaction between channels mediating potassium (Ito) and sodium (INa) currents has been suggested to be involved in the two main arrhythmogenic mechanisms: repolarization disorder and conduction disorder hypothesis. Thus, is it possible that the regulation of ion channel subunits mediating these two major currents of the cardiac action potential is coordinated? Notably, our recent work was the first to support this provocative idea that the expression of the depolarizing sodium channel and the repolarizing potassium channel Ito may share a common, yet to be identified, regulatory mechanism. Following gene silencing of KChIP2, an accessory subunit of Ito, the applicant found that the expression of Ito and INa was abolished producing a non-excitable cardiac myocytes. This suggested that the regulation of ion channel mediating these two major currents could be coordinated. This would represent a paradigm-shifting concept regarding ion channels expression and regulation. Therefore, we hypothesize that KChIP2 controls the expression of depolarizing (INa) and repolarizing (Ito) currents through multiple regulatory mechanisms. The specific aims of this proposal are to: 1. Identify genes modulated by KChIP2. 2. Determine if the regulation of INa and Ito involves microRNA(s). 3. Define the role of KChIP2 miRNA-dependent regulation in cardiac pathology. The delineation of the molecular basis of this regulation is essential for an accurate understanding of cardiac ventricular depolarization and repolarization and its derangements that are associated with lethal ventricular arrhythmias. Further functional dissection of KChIP2 will provide insight into numerous aspects of cardiac function will illuminate the role of the KChIP2 family of proteins in disease and likely unveil novel paradigms for ion channel function in health and disease.