Calmodulin Regulation Na Channels: From Function and Structure to Disease

钙调蛋白调节 Na 通道：从功能和结构到疾病

• 批准号: 9247246
• 负责人: Richard Aldrich
• 金额: $ 105.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247246
• 关键词: Action Potentials; Adult; Affinity; Alanine; Arrhythmia; Attenuated; Binding; Biological Assay; Calmodulin; Cardiac; Cardiac Myocytes; Complex; Custom; Data; Data Set; Disease; Disease model; Electrophysiology (science); Foundations; Heart Diseases; Human; Inherited; Knock-in; Knowledge; Long QT Syndrome; Maps; Measures; Mediating; Methods; Modeling; Molecular; Morphology; Mus; Muscle Cells; Mutation; Myocardium; Myotonia; Neonatal; Optics; Penetrance; Phase; Physiological; Prevalence; Probability; Publishing; Rattus; Regulation; Resolution; Role; Scanning; Seasons; Seminal; Skeletal Muscle; Structure; Tail; Testing; Therapeutic; Transgenic Mice; Ursidae Family; Variant; Ventricular; Work; base; design; induced pluripotent stem cell; inducible gene expression; multidisciplinary; mutant; overexpression; public health relevance; role model; single molecule; skeletal; targeted delivery; theories

 DESCRIPTION (provided by applicant): Nav channels figure crucially in cardiac and skeletal muscle. It is fitting then that channelopathic mutations throughout Nav1.5 (cardiac) and Nav1.4 (skeletal) channels, particularly in their carboxy tails (CTs), give rise to numerous arrhythmias and myotonias. Exploring such channelopathic disease will likely provide a clearer path towards understanding and developing new treatments for acquired arrhythmias of widespread prevalence. However, the actual changes in channel function and structure that result in even these channelopathic forms of disease have lacked a general understanding and deep foundational theory. Here, just published discoveries from our labs suggest a potentially transformational hypothesis that many of these channelopathic mutations act by weakening the binding of Ca2+-free calmodulin (apoCaM) to Nav channels, and that the absence of apoCaM on channels induces altered gating that directly accounts for the electrophysiological substrates underlying Brugada and long QT syndromes. Moreover, we have recently published the first atomic structure of apoCaM alone complexed with the CT of Nav1.5, allowing apoCaM modulation of Nav channel to be explored from an unprecedented structural perspective. Accordingly, we propose to combine single molecule functional analysis of Na channels, atomic structure of Na channels, and state-of-the-art cardiac disease models to understand and ultimately treat a broad class of Na channelopathic disease. In particular, this schema points naturally to new proof-of-principle therapeutic directions that will be investigated in this proposl. Overall, this genuinely multidisciplinary proposal, hosted by a seasoned and synergistic team, promise mechanistically deep advances towards understanding and treating forms of Brugada and long QT syndromes, and perhaps their related maladies of more general prevalence.

 描述(由申请人提供)：NAV通道在心肌和骨骼肌中起关键作用。因此，在整个NaV1.5(心脏)和Nav1.4(骨骼)通道中，特别是在它们的羧基尾巴(CT)中，通道病变突变会导致大量的心律失常和肌强直，这是合适的。探索这种通道性疾病可能会为理解和开发广泛流行的获得性心律失常的新疗法提供一条更清晰的途径。然而，甚至导致这些经络病态疾病的经络功能和结构的实际变化也缺乏普遍的理解和深刻的基础理论。在这里，我们实验室刚刚发表的发现提出了一个潜在的变革性假设，即许多这些通道病变突变的作用是通过削弱无钙钙调素(ApoCaM)与NAV通道的结合来发挥作用，并且通道上缺乏apoCaM会导致门控改变，这直接解释了Brugada和长QT综合征的电生理底物。此外，我们最近发表了第一个apoCaM单独与NaV1.5的CT复合的原子结构，使我们能够从前所未有的结构角度来探索apoCaM对NAV通道的调制。因此，我们建议结合钠通道的单分子功能分析、钠通道的原子结构和最先进的心脏病模型来了解并最终治疗一大类钠通道病。特别是，这一方案自然指向新的原则证明治疗方向，将在本提案中进行研究。总体而言，这项由经验丰富和协同的团队主持的真正多学科的提案承诺在机械上深入了解和治疗各种形式的Brugada和长QT间期综合征，或许是它们更普遍流行的相关疾病。