Molecular Mechanisms of Caton Channel Selectivity

离子通道是控制K+、Na+、Ca*+和CI等离子流动的膜蛋白 细胞膜。它们调节许多生物过程，如神经和肌肉的兴奋 细胞、荷尔蒙的分泌和感觉传导。在人类体内，几乎所有组织中都有它们的存在。 服务于各种任务。由于它们在人体中的普遍存在和重要性，离子通道 功能障碍通常是一系列人类疾病的核心。 离子选择性，通道只允许特定的离子通过它们的孔，而 不包括所有其他，是定义离子通道的特征属性之一。理解这一点 过程是获得与通道相关的生物活动的基本知识的核心 疾病。尽管在过去五年里在理解K+方面取得了巨大的进步 选择性，特别是随着几个K+通道结构的确定，几乎没有结构性 可用于任何其他阳离子通道的信息 我研究的总体目标是了解阳离子通道选择性的结构基础。 更具体地说，我的实验室将重点研究两组阳离子通道的选择性：非 特殊的阳离子通道，利用细菌Na+和K+传导的蜡状芽孢杆菌的NaK通道 与CNG通道的孔同源的通道，作为模型系统；原核电压- 门控Na+通道。我们将使用结晶学和电生理工具的组合来 从结构和功能两个方面描述这些渠道。拟议的研究有三个具体的 目标。第一个具体目标是研究NaK中一价阳离子传导的结构和功能 频道。这项研究将使我们能够阐明NaK离子通透性的分子机制， 这也将为理解CNG中离子选择性的结构基础提供重要的见解 频道大家庭。我们的第二个具体目标是研究NAK通道的二价阳离子堵塞。这 研究将阐明CNG通道二价阳离子阻断的潜在机制，这是一个 重要的生理意义，尤其是对视觉传导。第三，我们的目标是确定晶体 原核生物电压门控钠离子通道离子传导孔的结构。这项研究不仅将 使我们能够阐明钠离子通道中离子选择性的结构基础，但也将有助于阐明离子 钙离子通道的选择性，其选择性过滤器与钠离子通道具有很高的序列同源性。

Ion channels are membrane proteins that control the flow of ions such as K+, Na+, Ca*+, and CI" across the cell membrane. They regulate many biological processes such as the excitation of nerve and muscle cells, the secretion of hormones, and sensory transduction. In humans, they are found in nearly all tissues serving a variety of tasks. Because of their prevalence and importance in the human body, ion channel dysfunction often lies at the heart of a wide range of human pathologies. Ion selectivity, whereby channels only allow the passage of specific ions through their pores while excluding all others, is one of the characteristic properties defining an ion channel. Understanding this process is central to gaining fundamental knowledge about channel-related biological activities and diseases. Even though tremendous progress has been made over the last five years in understanding K+ selectivity, especially with the structure determination of several K+ channels, there is little structural information available for any other cation channels The overall goal of my research is to understand the structural basis of cation channel selectivity. More specifically, my laboratory will focus on studying the selectivity of two groups of cation channels: non specific cation channels, using the NaK channel from Bacillus cereus, a bacterial Na+ and K+ conducting channel that is homologous to the pore of a CNG channel, as a model system; and the prokaryotic voltage- gated Na+ channels. We will use a combination of crystallographic and electrophysiological tools to characterize these channels both structurally and functionally. The proposed research has three specific aims. The first specific aim is the structural and functional study of monovalent cation conduction in the NaK channel. This study will allow us to elucidate the molecular mechanisms underlying ion permeability in NaK, and will also provide crucial insights into understanding the structural basis of ion selectivity in the CNG channel family. Our second specific aim is to study the divalent cation blockage of the NaK channel. This study will elucidate the underlying mechanism of divalent cation blockage in CNG channels, a process of crucial physiological significance, especially to visual transduction. Third, we aim to determine the crystal structure of the ion conduction pore of a prokaryotic voltage-gated Na+ channel. This study will not only allow us to elucidate the structural basis of ion selectivity in Na* channels, but will also shed light on the ion selectivity of Ca2+ channels whose selectivity filter shares high sequence homology to that of Na* channels.