Molecular Mechanisms of Caton Channel Selectivity

阳离子通道选择性的分子机制

• 批准号: 7316422
• 负责人: YOUXING JIANG
• 金额: $ 27.48万
• 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/7316422
• 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; Range; 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

DESCRIPTION (provided by applicant): Ion channels are membrane proteins that control the flow of ions such as K+, Na+, Ca2+, 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.

描述（由申请人提供）：离子通道是控制跨细胞膜的离子流动（例如K+，Na+，Ca2+和CI-）流动的膜蛋白。它们调节许多生物学过程，例如神经和肌肉细胞的激发，激素的分泌以及感觉转导。在人类中，几乎所有的组织都发现了它们。由于它们在人体中的普遍性和重要性，因此离子通道功能障碍通常位于多种人类病理的核心。离子选择性，即通道仅允许特定离子通过其毛孔通过，而排除所有其他离子则是定义离子通道的特征属性之一。了解这一过程对于获得有关渠道相关的生物学活动和疾病的基本知识至关重要。尽管过去五年来在理解K+选择性方面取得了巨大进展，尤其是在几个K+渠道的结构确定的情况下，其他任何其他阳离子渠道的结构信息很少，我的研究的总体目标是了解结构基础阳离子通道的选择性。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：非特定阳离子通道，使用蜡状芽孢杆菌的NAK通道，一种细菌Na+和K+导电通道，与CNG通道的孔同源，作为CNG通道的孔。模型系统；和原核电压通道的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。拟议的研究具有三个具体目标。第一个具体目的是NAK通道中单价阳离子传导的结构和功能研究。这项研究将使我们能够阐明NAK中离子渗透性的分子机制，并且还将为理解CNG通道家族中离子选择性的结构基础提供关键见解。我们的第二个具体目的是研究NAK通道的二价阳离子阻塞。这项研究将阐明CNG通道中二价阳离子阻塞的潜在机制，这是一个至关重要的生理意义的过程，尤其是对于视觉转导的过程。第三，我们的目的是确定原核电压门控Na+通道的离子传导孔的晶体结构。这项研究不仅将使我们能够在Na*通道中阐明离子选择性的结构基础，而且还可以阐明Ca2+通道的离子选择性其选择性过滤器与Na*通道的离子选择性高序列同源。