Loss of muscle excitability in acute quadriplegic myopathy

描述(申请人提供)：危重病患者由于骨骼肌兴奋性丧失而出现瘫痪(危重病肌病，CIM)。在CIM的动物模型中，钠通道失活的电压依赖的超极化漂移被发现是兴奋性丧失的基础。在研究CIM中钠通道门控缺陷的过程中，发现了几个快速调节钠通道门控电压依赖性的过程(像CIM那样是几分钟而不是几天)。一种过程是保持电位引起钠通道门控的电压依赖性的移动。第二个过程是损伤诱导的钠通道门控电压依赖的超极化漂移。本研究的目标是确定钠通道门控电压依赖的快速变化和CIM中发展的较慢变化的机制和功能。电生理学和生物化学相结合的方法将被用来确定已经确定的钠通道门控电压依赖的各种变化的潜在机制。将使用计算机建模来探索已确定的门控变化的潜在功能后果。虽然这项工作的目标是开发CIM的治疗方法，但调节钠通道门控电压依赖性的通路的识别对其他兴奋性疾病的治疗具有重要意义，如癫痫和心律失常。

DESCRIPTION (provided by applicant): 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. Computer modeling will be employed to explore potential functional consequences of gating changes 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.