SLOW INACTIVATION OF SODIUM CHANNELS

描述：这项提议的广泛、长期目标是 为了刻画部分的结构-功能关系 控制缓慢失活的钠通道及其相互作用 与其他渠道功能，并最终定义如何 经络结构的异常可能导致疾病状态，如 癫痫和周期性瘫痪。 具体目标是：1)制作、表达和比较野生型和 突变的钠通道以确定通道分子的哪一部分 控制缓慢激活；以及2)确定 缓慢失活和激活之间的相互作用。 这项提议与健康的相关性在于它适用于 神经元兴奋性。神经细胞中的一个关键因素 过度兴奋(可能导致癫痫和其他疾病 包括失去对细胞兴奋性的控制)是去极化 在F(VH)曲线的中点和斜率的增加，这导致 可用于激活的频道数量从 静息潜力。 记录宏观钠电流和单通道电流 表达野生型和突变型钠通道的非洲爪哇卵母细胞 使用膜片钳技术。缓慢的失活特性， 包括F(VH)曲线的价态和中点以及慢速 将比较失活开始时间和失活恢复率 野生型和钠通道突变体。激活电压依赖关系 和动力学、快速失活动力学和通道渗透 还将对物业进行监测，以评估其他潜力 引入突变的后果。

DESCRIPTION: The broad, long-term objectives of this proposal are to characterize the structure-function relationship of the parts of sodium channels that control slow inactivation and its interactions with other channel functions, and to ultimately define how abnormalities in channel structure might lead to disease states like epilepsy and the periodic paralyses. The specific aims are: 1) to make, express and compare wildtype and mutant sodium channels to determine which part of the channel molecule controls slow activation; and 2) to determine the nature of interaction between slow inactivation and activation. The health-relatedness of this proposal is in its application to neuronal excitability. One critical factor in neuronal hyperexcitability (that could lead to epilepsy and other diseases involving loss of control over cell excitability) is a depolarization in the midpoint and increase in slope of the F(Vh) curve which leads to an increase in the number of channels available for activation from resting potential. Macroscopic sodium currents and single channel currents will be recorded from Xenopus oocytes expressing wild-type and mutant sodium channels using the patch clamp technique. Slow inactivation properties, including valence and midpoint of the F(Vh) curve as well as slow inactivation onset and recovery rates will be compared between wildtype and sodium channel mutants. Activation voltage dependence and kinetics, fast inactivation kinetics and channel permeation properties will also be monitored to assess other potential ramifications of introduced mutations.