Permeation of Inward Rectifier K+ Channels

描述（由申请人提供）：我的研究的长期目标是 了解K约渠道的机制，一组高度多样化的 整合膜蛋白。一类特殊的K+通道，称为内向型， 整流器，通过K+离子在向内的方向上比在 向外的方向。这种特性称为向内整流， 内向整流钾通道维持和调节静息膜 因此，它可以完成许多重要的生物学任务。的 这里提出的实验主要是为了了解机制 潜在的内向整流，即，这些通道是如何被 细胞内阳离子 这些通道将在非洲爪蟾卵母细胞中表达，并且它们的功能 将使用电生理技术检查性能， 结合诱变。目的1：了解内向型糖尿病的机制 整流块细胞内阳离子，我们将确定：a）动力学 细胞内多胺阻断通道的机制，B） 赋予向内整流器与 细胞内多胺，和c）潜在的分子机制， 通道对细胞内阳离子的特异性。在目标2中，我们将使用 细菌K+通道（KcsA）的传导孔-其结构已被 用X-射线衍射测定-作为模型，以进一步研究的机制 通过该通道实现细胞内的高亲和力结合， 阳离子。 这些研究具有重要的医学意义。内向整流钾离子 通道发挥许多重要的生物学作用，例如，它们调节控制 迷走神经对心率的影响，调节神经系统中的突触传递 系统，并将血糖水平与胰岛素分泌相结合。因此这些 通道代表了医学干预的重要药理学靶点 在各种疾病状态下。

DESCRIPTION (provided by applicant): The long term goal of my research is to understand the mechanisms of K about channels, a group of highly diversified integral membrane proteins. A special class of K+ channels, called inward about rectifiers, pass K+ ions in the inward direction more efficiently than in the outward direction. This property, referred to as inward rectification, allows inward-rectifier K+ channels to maintain and regulate the resting membrane potential and thereby accomplish many important biological tasks. The experiments proposed here are primarily aimed to understand the mechanisms underlying inward rectification, i.e., how the channels are blocked by intracellular cations. The channels will be expressed in Xenopus oocytes and their functional properties will be examined using electrophysiological techniques in conjunction with mutagenesis. Aim 1: To understand the mechanisms of inward rectifier block by intracellular cations we will determine: a) the kinetic mechanism of channel block by intracellular polyamines, b) the mechanism which confers high affinity to the interaction of inward rectifiers with intracellular polyamines, and c) the molecular mechanism underlying the channel's specificity for intracellular cations. In Aim 2, we will use the conduction pore of a bacterial K+ channel (KcsA)-whose structure has been determined with X-ray diffraction-as a model to further examine the mechanism by which the channel achieves the high-affinity binding of intracellular cations. The proposed studies have important medical implications. Inward-rectifier K+ channels play many important biological roles, e.g., they mediate the control of heart rate by the vagus nerve, modulate synaptic transmission in the nervous system, and couple blood glucose levels to insulin secretion. Thus, these channels represent important pharmacological targets for medical intervention during various disease states.