Basic Mechanisms of Ion Channel Function

描述：这项研究的重点是了解基本化学 K+通道蛋白的作用机制。近原子分辨率结构 离子通道及其分离结构域的研究， 我将利用我们对这些结构的新知识来提出关于K+的问题 渠道机制特别是，拟议的工作是针对两个K+ 通道-细菌通道KcsA，它产生了前所未有的洞察力 进入离子选择性的化学，和振荡器，一个研究充分的“千伏”型 代表神经系统中许多同源通道的通道。KcsA 可以高水平表达，并在生物化学定义的，纯化的 系统.我们将通过以下方式展示KcsA的基本离子渗透性能： 记录重构膜中的单通道。利用这个系统，我们 将研究的原因，奇怪的形状的渗透途径，重点 特别是关于离子传输的静电学。我们将使用磁性 共振方法来直接测量离子与孔的结合。此外，本发明还提供了一种方法， 我们将试图了解Shaker K+通道的分子结构， 通过设计用于测量特定物体之间距离的技术组合， 渠道的区域。这项研究并不针对任何特定的 疾病相关的问题;这是核心作用，K+通道在 几乎所有的人类生理学，使这项基础研究与人类有关， 一般健康。

DESCRIPTION: This research is focused on understanding the basic chemical mechanisms by which K+ channel proteins work. Near atomic-resolution structures are emerging for ion channels and for isolated domains thereof, and this work will exploit our new knowledge of these structures in asking questions about K+ channel mechanisms. In particular, the proposed work is aimed at two K+ channels - the bacterial channel KcsA, which has produced unprecedented insight into the chemistry of ion selectivity, and Shaker, a well-studied "Kv"-type channel representative of many homologous channels in the nervous system. KcsA may be expressed at high levels and studied in biochemically defined, purified systems. We will lay out the basic ion permeation properties of KcsA by recording single channels in reconstituted membranes. Using this system, we will examine the reasons for the odd shape of the permeation pathway, focusing particularly on the electrostatics of ion transport. We will use magnetic resonance methods to directly measure binding of ions to the pore. In addition, we will attempt to understand the molecular architecture of Shaker K+ channels by a combination of techniques designed to measure distances between specific regions of the channel. This research is not directed towards any particular disease-related problem; it is the central roles that K+ channels play in virtually all human physiology that make this basic research relevant to human health in general.