MOLECULAR BASIS OF MEMBRANE EXCITABILITY

对神经、心脏和肌肉细胞的功能至关重要的是， 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。 在易兴奋细胞中， 即使在一群神经元中， 频率，以及这些动作电位的形状和持续时间 广泛地。 这个项目的目标是了解这些 在电压门控离子的特定亚型方面的差异 细胞表达的通道。 离子通道是膜蛋白 通过调节离子流产生动作电位信号 穿过细胞膜 它们有多种类型，通常是 以它们最具选择性的离子种类命名。 内 Na、K和Ca通道的种类， 通道亚型通过生物物理学、药理学 或结构性差异。 虽然在这方面取得了迅速进展， 表征这些差异并阐明潜在的分子 结构，令人惊讶的是，很少有人知道这些亚型 这些差异导致了 它们在其中表达。 娜更是如此 有六种或更多亚型的通道，但它们最初似乎都是 看起来有同样的功能。 一个重要的线索来自 这些通道亚型的分布。 在感觉神经元中， TTX-不敏感（TTX-i）Na通道总是与缓慢的- 激活（慢）K通道，产生动作电位， 相对较长的持续时间。 相反，快速激活（快速）K通道 只在同样只表达快速TTX的细胞中表达， Na通道的敏感（TTX-s）亚型，产生短期作用 潜力 感觉神经元的第三个子集只表达 TTX-s NA通道沿着与慢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通道亚型的表达如何与 与已知发生在细胞中的特定钙通道亚型的表达有关， 这些神经元。 此外，这些离子的功能含义 将研究信道子类型关联。 例如， 动作电位特性和动态放电的差异 不同细胞亚群利用的特征？ 有 确定不同通道的子类型的一般原则 在同一个细胞中共同表达？ 这些原则和 在其他组织中发现的相关亚型的相似关联？ 是 这些协会以类似的方式被剥削？

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?