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: 9104702
• 负责人: Richard Aldrich
• 金额: $ 107.27万
• 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/9104702
• 关键词: Accounting; Action Potentials; Adult; Affinity; Alanine; Arrhythmia; Attenuated; Binding; Biological Assay; Calmodulin; Cardiac; Cardiac Myocytes; Complex; Custom; Data; Data Set; Disease; Disease model; Electrophysiology (science); Heart Diseases; Human; Inherited; Knock-in; Knowledge; Long QT Syndrome; Maps; Measures; Mediating; Methods; Modeling; Molecular; Morphology; Mus; Muscle Cells; Mutation; Myocardium; 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; 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（由适用提供）：NAV通道完全在心脏和骨骼肌中。当时，NAV1.5（心脏）和NAV1.4（骨骼）通道（尤其是在其羧基尾巴（CTS）中）中的通道疗法突变很适合，引起了许多心律不齐和肌肉发达。探索这种通道性疾病可能会为理解和开发新的治疗方法提供更明显的途径，以实现获得宽度流行率的心律不齐。但是，即使导致这些通道疾病形式的通道功能和结构的实际变化也缺乏一般的理解和深刻的基础理论。 Here, just published discoveries from our labs suggest a potentially transformative 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 influences altered gating that directly accounts for the electrophysiological substrates underlying Brugada and long QT syndromes.此外，我们最近发表了第一个与NAV1.5 CT复合的启动的第一个原子结构，从而可以从前所未有的结构观点探索NAV通道的启示录。根据，我们建议将NA通道，NA通道的原子结构和最新心脏病模型的单分子功能分析结合在一起，以了解并最终治疗广泛的NA通道病毒疾病。特别是，这种模式自然指向了将在此提案中调查的新原则治疗方向。总体而言，这一由经验丰富且协同的团队主持的真正多学科的建议有望在理解和治疗Brugada和Long QT综合症的形式方面进行机械深刻的进步，以及他们对更普遍流行的相关疾病。