Loss of muscle excitability in acute quadriplegic myopathy

描述（由申请人提供）：危重症患者因骨骼肌兴奋性丧失而瘫痪（危重症肌病，CIM）。在CIM的动物模型中，发现钠通道失活的电压依赖性的超极化移位是兴奋性丧失的基础。在对CIM中钠通道门控缺陷的研究过程中，确定了几个快速调节钠通道门控电压依赖性的过程（在几分钟内而不是在CIM中几天）。其中一个过程是在钠通道门控的电压依赖性中产生保持电位诱导的移位。第二个过程是钠通道门控电压依赖性的损伤诱导的超极化移位。当前提案的目标是确定钠通道门控电压依赖性的快速变化以及CIM中发展的较慢变化的机制和功能。结合电生理和生化的方法将被用来确定已经确定的钠通道门控电压依赖性的各种变化的机制。计算机建模将用于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，但确定调节钠通道门控电压依赖性的途径对治疗其他兴奋性疾病（如癫痫和心律失常）具有重要意义。

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.