Molecular Mechanisms of Caton Channel Selectivity

阳离子通道选择性的分子机制

• 批准号: 7683886
• 负责人: YOUXING JIANG
• 金额: $ 27.06万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683886
• 关键词: Affinity; Amino Acids; Bacillus cereus; Binding; Binding Sites; Biological; Biological Assay; Biological Models; Biological Process; Cations; Cell membrane; Cell secretion; Characteristics; Disease; Divalent Cations; Family; Focus Groups; Functional disorder; Goals; Heart; Hormones; Human; Human Pathology; Human body; Ion Channel; Ions; Knowledge; Laboratories; Light; Membrane; Membrane Proteins; Molecular; Monovalent Cations; Muscle Cells; Mutagenesis; Nerve; Permeability; Phototransduction; Physiological; Potassium Channel; Prevalence; Process; Property; Research; Research Personnel; Resolution; Sensory; Sequence Homology; Structure; System; Tissues; Voltage-Gated Potassium Channel; base; cyclic-nucleotide gated ion channels; extracellular; insight; mutant; programs; tool; voltage

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.

离子通道是控制离子流动（例如K+，Na+，Ca*+和Ci）的膜蛋白。 细胞膜。他们调节许多生物学过程，例如神经和肌肉的激发 细胞，激素的分泌和感觉转导。在人类中，几乎所有组织都发现它们 服务各种任务。由于它们在人体中的普遍性和重要性，离子渠道 功能障碍通常位于多种人类病理的核心。 离子选择性，通道仅允许特定离子通过其毛孔通过 除其他所有内容外，是定义离子通道的特征属性之一。了解这一点 过程对于获得有关渠道相关的生物学活动的基本知识和 疾病。尽管过去五年来在理解K+方面取得了巨大进展 选择性，尤其是在几个K+通道的结构确定的情况下，几乎没有结构 任何其他阳离子渠道可用的信息 我的研究的总体目标是了解阳离子渠道选择性的结构基础。 更具体地说，我的实验室将专注于研究两组阳离子通道的选择性：非 特定的阳离子通道，使用蜡状芽孢杆菌的NAK通道，细菌Na+和K+导电 与CNG通道的孔同源的通道，作为模型系统；和原核电压 - 门控na+通道。我们将使用晶体学和电生理工具的组合来 在结构和功能上表征这些通道。拟议的研究有三个特定的 目标。第一个具体目的是NAK中单价阳离子传导的结构和功能研究 渠道。这项研究将使我们能够阐明Nak中离子渗透性的分子机制， 并且还将为了解CNG中离子选择性的结构基础提供关键见解 渠道家庭。我们的第二个具体目的是研究NAK通道的二价阳离子阻塞。这 研究将阐明CNG通道中二价阳离子阻塞的潜在机制， 至关重要的生理意义，尤其是视觉转导。第三，我们旨在确定晶体 原核力电压门控的Na+通道的离子传导孔的结构。这项研究不仅会 允许我们在Na*通道中阐明离子选择性的结构基础，但也会忽略离子 Ca2+通道的选择性具有选择性过滤器与Na*通道的选择性高序列同源性。