Calmodulin Regulation Na Channels: From Function and Structure to Disease

 描述（由申请人提供）：Nav通道在心肌和骨骼肌中至关重要。因此，贯穿Nav1.5（心脏）和Nav1.4（骨骼）通道的通道病变突变，特别是在它们的羧基尾（CT）中，引起许多心律失常和肌强直是合适的。探索这种通道病可能会提供一个更清晰的途径，了解和开发新的治疗广泛流行的获得性心律失常。然而，通道功能和结构的实际变化，甚至导致这些通道病变形式的疾病，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转型假设，即许多这些通道病变突变通过削弱无钙钙调蛋白（apoCaM）与Nav通道的结合而起作用，并且通道上缺乏apoCaM会导致门控改变，直接解释Brugada和长QT综合征的电生理底物。此外，我们最近发表了apoCaM单独与Nav1.5的CT复合的第一个原子结构，允许从前所未有的结构角度探索apoCaM对Nav通道的调节。因此，我们建议将Na通道的单分子功能分析、Na通道的原子结构和最先进的心脏病模型相结合，以了解并最终治疗广泛的Na通道病。特别是，这种模式自然指向新的证明原则的治疗方向，将在这个proposl调查。总的来说，这个真正的多学科的建议，由一个经验丰富的和协同的团队主持，承诺机械深入的进步，了解和治疗形式的Brugada和长QT综合征，也许他们的相关疾病的更普遍的患病率。

 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.