Loss of muscle excitability in acute quadriplegic myopathy

危重患者由于骨骼肌兴奋性丧失(危重疾病)而出现瘫痪 肌病，CIM)。在CIM动物模型中，钠离子电压依赖性的超极化漂移 通道失活被发现是兴奋性丧失的基础。在钠通道门控的研究中 在CIM中，发现了几个快速调节钠的电压依赖性的过程 频道选通(几分钟，而不是像CIM中的几天)。一种过程是由保持电位引起的 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变化。当前提案的目标是确定 钠通道门控AS电压依赖性快速变化的机制和作用 以及在CIM中发展的较慢的转变。电生理和生物化学相结合的方法将 用来确定钠离子电压依赖性不同变化的机制 已标识的通道选通。虽然这项工作的目标是开发CIM的治疗方法，但 识别调节钠通道门控电压依赖性的通路具有重要意义 用于治疗其他兴奋性疾病，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.