Loss of muscle excitability in acute quadriplegic myopathy

重症患者由于骨骼肌兴奋性丧失而发生瘫痪（危重病 肌病，CIM）。在CIM的动物模型中，钠的电压依赖性的超极化转变， 发现通道失活是兴奋性丧失的基础。在钠通道门控研究期间 CIM中的缺陷，几个过程被确定为快速调节钠的电压依赖性 通道门控（在数分钟内，而不是在CIM中的数天）。一个过程是保持电位引起的偏移， 钠通道门控的电压依赖性。第二个过程是损伤诱导的超极化 钠通道门控的电压依赖性的偏移。目前提案的目标是确定 钠通道门控的电压依赖性的快速变化的机制和功能 以及CIM发展的缓慢转变。结合电生理和生物化学方法将 用于确定钠的电压依赖性的各种变化的机制 已识别的通道门控。虽然这项工作的目标是为CIM开发治疗方法， 确定调节钠通道门控电压依赖性的途径具有重要意义 用于治疗其他兴奋性疾病，例如癫痫和心律失常。

Critically ill patients develop paralysis due to loss of skeletal muscle excitability (critical illness myopathy, CIM). In an animal model of CIM, a hyperpolarized shift in the voltage dependence of sodium channel inactivation was found to underlie loss of excitability. During investigation of sodium channel gating defects in CIM, several processes were identified that rapidly modulate the voltage dependence of sodium channel gating (over minutes rather than days as in CIM). One process is a holding potential induced shift in the voltage dependence of sodium channel gating. A second process is a damage-induced, hyperpolarized shift in the voltage dependence of sodium channel gating. The goal of the current proposal is to determine the mechanism and function of both the rapid shifts in the voltage dependence of sodium channel gating as well as the slower shift that develops in CIM. Combined electrophysiologic and biochemical approaches will be used to determine the mechanisms underlying the various shifts in the voltage dependence of sodium channel gating that have been identified. While the goal of this work is to develop therapy for CIM, the identification of pathways that modulate the voltage dependence of sodium channel gating has implications for treatment of other disorders of excitability such as epilepsy and cardiac arrhythmia.