Regulation and dysregulation of sodium channels by by calmodulin

项目摘要 在美国，心脏性猝死是死亡的主要原因，通常是由心脏病引起的 心律不齐。钠通道的突变，特别是在其羧基末端区域(CTD)，失调节拍- 抑制钠和钙的循环，从而引发心律失常。同样，钙调蛋白(CaM)的突变， 密切调节这些通道的，也与心律失常有关。然而，钠通道在肌动蛋白中的作用 心律失常的发生机制尚不清楚。NavCTD突变会改变Nav Cam的亲和力，损害FAST 失活并诱发心律失常的晚NAV电流(INA)。对于NAV亚型来说，这一点尤其明显 表现出最低的CaM亲和力，相应地，相对于峰值Ina，后期的Ina星等最大。我们的 最近的研究表明，这些NAV亚型在晚期INA介导的心律失常中起着重要作用。然而， NaV失调对钙调蛋白驱动的心律失常的致心律失常作用尚不清楚。基于强大的 来自我们实验室的初步数据，我们假设CaM对Nav的亲和力将决定 致心律失常迟发性心绞痛。减少CaM与NavCTD的结合将增加后期INA，而增强结合 会加速通道失活，减轻晚期室性心律失常。因此，我们建议：1)评估程度和 钙调素调节NAV失调的机制。2)阐明突变体CaM介导的NAV的相对贡献 钙调素病相关心律失常的功能障碍。3)检测增强的抗心律失常潜能 凸轮-导航交互。因此，通过了解钙调蛋白病变，我们的目标是发现预防 CaM-NAV相互作用异常和NAV功能异常所致的心律失常。

Project Summary Sudden cardiac death is a leading cause of mortality in the United States and often results from cardiac arrhythmias. Mutations in Na+ channels, particularly in their carboxy terminal domains (CTDs), dysregulate beat- to-beat cycling of Na+ and Ca2+, and thereby, precipitate arrhythmias. Similarly, mutations in calmodulin (CaM), which closely regulates these channels, are also linked to arrhythmias. However, the role of Na+ channels in arrhythmogenesis remains unclear. NavCTD mutations, which alter the affinity of Nav CaM, impair fast inactivation and induce proarrhythmic late Nav current (INa). This particularly is evident for Nav isoforms which exhibits the lowest CaM affinity and correspondingly, the largest of late INa magnitude relative to peak INa. Our recent studies indicate an important role for these Nav isoforms in late INa-mediated arrhythmias. However, the arrhythmogenic impact of Nav dysregulation in calmodulin-driven arrhythmias remains unclear. Based on strong preliminary data from our laboratory, we hypothesize that affinity of CaM for Nav will dictate the magnitude of arrhythmogenic late INa. Diminished CaM binding to the NavCTD will increase late INa, while enhanced binding will hasten channel inactivation, mitigating proarrhythmic late INa. Thus, we propose to: 1) Assess the extent and mechanism of NaV dysregulation by CaM. 2) Elucidate the relative contribution of mutant CaM-mediated Nav dysfunction to calmodulinopathy associated arrhythmias. 3) Examine the antiarrhythmic potential of enhancing CaM-Nav interaction. Thus, by understanding calmodulinopathies, we aim to discover approaches to prevent arrhythmias stemming from both aberrant CaM-NaV interaction and abnormal NaV function.