MOLECULAR BASIS OF MEMBRANE EXCITABILITY

对神经、心脏和肌肉细胞的功能至关重要的是快速 以频率和持续时间编码的信息的传输 称为动作电位的电脉冲。在可兴奋的细胞和 即使在一群神经元中，最大动作电位放电 频率，这些动作电位的形状和持续时间各不相同 广泛地。本项目的目标是了解这些 电压门控离子的特定亚型的差异 由细胞表达的通道。离子通道是膜蛋白 通过调节离子的流动来产生动作电位信号 穿过薄膜。它们有各种各样的类型，通常是 以它们最具选择性的离子物种命名。在 钠、钾和钙通道的种类，迅速增加的数量 通过生物物理、药理学来区分经络亚型 或者结构性差异。尽管在以下方面正在取得快速进展 表征这些差异并阐明潜在的分子 结构，令人惊讶的是，关于这些子类型是如何 差异导致了 表达它们的细胞。对于Na来说尤其如此 有六个子类型或更多子类型的频道，但一开始看起来都是 一目了然地具有相同的功能。一条重要的线索来自 这些渠道亚型的分布。在感觉神经元中，慢的， 河豚毒素不敏感(TTX-I)钠通道总是与慢- 激活(慢)K通道，产生动作电位 持续时间相对较长。相反，快速激活(快速)K通道 仅在也只表达FAST、TTX-的细胞中表达 钠通道敏感亚型(河豚毒素-S)，产生短时动作 潜力。第三个感觉神经元子集只表达 河豚毒素-S NA通道与慢K通道一起，产生作用 中等持续时间的潜力。拟议的研究将 研究这些Na和K通道亚型的表达是如何相关的 对已知的发生在 这些神经元。此外，这些离子的功能含义 将研究渠道亚类型关联。比方说，他们的 动作电位特性与动态放电的差异 细胞的不同子集所利用的特征？在那里吗 确定不同渠道的哪些子类型的一般原则 物种在相同的细胞中共表达吗？这些原则和原则 在其他组织中发现的相关亚型的类似关联？是 这些关联被以类似的方式利用吗？

Essential to the function of nerve, heart and muscle cells is the rapid transmission of information encoded in the frequency and duration of electrical impulses called action potentials. Among excitable cells and even within a population of neurons, the maximal action potential firing frequency, and the shape and duration of those action potentials vary widely. The goal of this project is to understand these differences in terms of specific subtypes of voltage-gated ionic channels expressed by the cell. Ionic channels are membrane proteins that generate the action potential signal by regulating the flow of ions across the membrane. They come in a variety of types, that are typically named by the ion species that they are most selective for. Within the categories of Na, K and Ca channels, a rapidly increasing number of channel subtypes is being distinguished by biophysical, pharmacological or structural differences. Although rapid progress is being made in characterizing these differences and elucidating the underlying molecular structures, surprisingly little is known about how these subtype differences contribute to the essential functional differences of the cells in which they are expressed. This is especially true of Na channels which come in six or more subtypes, but which all seem at first glance to have the same function. An important clue comes from the distribution of these channel subtypes. In sensory neurons, the slow, TTX-insensitive (TTX-i) Na channels are always co-expressed with slowly- activating (slow) K channels, generating action potentials with relatively long durations. Conversely, fast-activating (fast) K channels are expressed only in cells that also express only the fast, TTX- sensitive (TTX-s) subtype of Na channel, generating short duration action potentials. A third subset of sensory neurons expresses only the TTX-s NA channel along with the slow K channel, generating action potentials of intermediate duration. The proposed research will investigate how the expression of these Na and K channel subtypes relates to the expression of specific Ca channel subtypes known to occur in these neurons. In addition, the functional implications of these ion channel subtype associations will be studied. For instance, how are the differences in action potential properties and dynamic firing characteristics exploited by different subsets of cells? Are there general principles that determine which subtypes of different channel species are co-expressed in the same cells? Are these principles and similar associations of related subtypes found in other tissues? Are these associations exploited in similar ways?