MOLECULAR PHYSIOLOGY OF NEUROMUSCULAR DISEASES

描述：肌强直和周期性麻痹是遗传性疾病， 骨骼肌，其中电压门控离子通道的突变改变了 肌膜的电兴奋性。 长期目标是 项目是表征突变通道的功能缺陷， 这些疾病，并确定如何异常通道行为产生 症状 高钾性周期性麻痹（HyperPP）、先天性副肌强直（PMC）和 钾加重肌强直（PAM）都是由我的错义突变引起的， 成人骨骼肌钠通道（SkM 1）的B亚单位。 通过 记录来自患者源性肌管或来自异源性肌管的Na电流 表达突变通道，我们和其他人已经表明， 在这些疾病中是快速失活的破坏。 目标1 建议是确定额外的功能缺陷， 未表征的突变，并进一步定义门控谱 缺陷 目标2旨在通过研究改善这些疾病的治疗 美西律（一种依赖于使用的阻滞剂）的作用机制， 乙酰唑胺对突变型钠通道的影响。 因为钠通道失活是一种 目的2中肌强直或麻痹倾向的关键决定因素 我们将进一步研究正常快 和使用半胱氨酸扫描诱变的慢失活， 提出的失活门（结构域III-IV之间的细胞质环）。 目标4 是确定Na通道门控中的主要缺陷如何导致 肌强直和周期性麻痹的不同表型。 战略 探索这些表型的病理生理基础是为了 进一步我们的肌肉兴奋性的计算机模拟，使用肌源性 表达系统，并开发基于动物的模型。 拟议的研究旨在提供更全面的了解 一组人类神经肌肉疾病的病理生理学基础： 从基因缺陷到临床症状 这些研究也将进一步促进我们的 在分子水平上了解Na通道功能，将识别 治疗患者的药理学策略，并将作为模型 了解更常见的兴奋性障碍的系统， 癫痫或心律失常。

DESCRIPTION: The myotonias and periodic paralyses are heritable diseases of skeletal muscle in which mutations of voltage-gated ion channels alter the electrical excitability of the sarcolemma. The long-term goals of this project are to characterize the functional defects of mutant channels in these disorders and to determine how abnormal channel behavior produces symptoms. Hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium-aggravated myotonias (PAM) are all caused my missense mutations in the b subunit of the adult skeletal muscle sodium channel (SkM1). By recording Na currents from patient-derived myotubes or from heterologously expressed mutant channels, we and other have shown that the primary defect in these diseases is disruption of fast inactivation. Aim 1 of this proposal is to identify the functional defects for additional, as-yet uncharacterized, mutations and to define further the spectrum of gating defects. Aim 2 seeks to improve the treatment of these diseases by studying the mechanism of action of mexiletine (a use-dependent blocker) and acetazolamide on mutant Na channels. Because Na channel inactivation is a critical determinant in the predilection for myotonia or paralysis, in Aim 2 we will further investigate the molecular mechanisms underlying normal fast and slow inactivation using cysteine-scanning mutagenesis within the proposed inactivation gate (cytoplasmic loop between domains III-IV). Aim 4 is to determine how primary defects in Na channel gating lead to the divergent phenotypes of myotonia and periodic paralysis. The strategy for exploring the pathophysiologic basis of these phenotypes is to refine further our computer simulation of muscle excitability, to use myogenic expression systems, and to develop animal-based models. The proposed studies are designed to provide a more complete understanding of the pathophysiologic basis for a group of human neuromuscular diseases: from gene defect to clinical symptoms. These studies will also further our knowledge of Na channel function at the molecular level, will identify pharmacological strategies for treating patients, and will serve as a model system for understanding more common disorders of excitability such as epilepsy or cardiac arrhythmia.