Regulation and dysregulation of sodium channels by by calmodulin

钙调蛋白对钠通道的调节和失调

• 批准号: 10673012
• 负责人: Przemyslaw Radwanski
• 金额: $ 49.29万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673012
• 关键词: Affect; Affinity; Animals; Anti-Arrhythmia Agents; Arrhythmia; Binding; Biochemical; Biological Assay; Calcium; Calmodulin; Cardiac; Cardiac Myocytes; Data; Disease; Electrophysiology (science); Exhibits; Functional disorder; Glean; Heart; Heart Diseases; Image; Impairment; In Vitro; Laboratories; Link; Mediating; Morbidity - disease rate; Mus; Mutation; Neurons; Phenotype; Protein Isoforms; Proteins; Regulation; Research; Role; RyR2; SCN8A gene; Secondary to; Sodium; Sodium Channel; Techniques; Testing; Transgenic Mice; Translating; United States; Variant; Viral; gain of function; heart rhythm; in vivo; insight; mortality; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; prevent; stem; sudden cardiac death

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.

项目摘要 心源性猝死是美国死亡率的主要原因，通常由心源性心脏病引起。 心律不齐Na+通道的突变，特别是其羧基末端结构域（CTD）的突变， Na+和Ca 2+的搏动循环，从而诱发心律失常。类似地，钙调蛋白（CaM）的突变， 密切调节这些通道，也与心律失常有关。然而，Na+通道在 胚胎发生仍不清楚。NavCTD突变改变了Nav CaM的亲和力， 失活并诱导亲核性晚Nav电流（INa）。这对于Nav同种型尤其明显， 表现出最低的CaM亲和力，相应地，相对于峰值INa，晚期INa幅度最大。我们 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重要作用。但 Nav失调对钙调素驱动性心律失常的致心律失常影响尚不清楚。基于强 根据我们实验室的初步数据，我们假设CaM对Nav的亲和力将决定 致炎性晚期INa。CaM与NavCTD结合减少将增加晚期INa，而结合增强 将加速通道失活，减轻促肾上腺皮质激素性晚期INa。因此，我们建议：（1）评估范围和 CaM引起的NaV失调的机制。2)阐明突变型CaM介导的Nav 钙调蛋白病相关的心律失常。3)检查增强的抗肿瘤潜力 CaM-Nav相互作用。因此，通过了解钙调蛋白病，我们的目标是发现预防的方法， 心律失常源于异常CaM-NaV相互作用和异常NaV功能。