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如K+、Na+、Ca ++和Cl-跨膜流动的膜蛋白。 细胞膜。它们调节许多生物过程，如神经和肌肉的兴奋 细胞、激素分泌和感觉传导。在人类中，它们几乎存在于所有组织中 服务于各种任务。由于它们在人体中的普遍性和重要性，离子通道 功能障碍通常是多种人类病理学的核心。 离子选择性，通道仅允许特定离子通过其孔， 是定义离子通道的特征性质之一。理解这一 这一过程是获得有关通道相关生物活动的基础知识的核心， 疾病尽管在过去的五年里，对K+的理解取得了巨大的进展， 选择性，特别是几个K+通道的结构测定，几乎没有结构 任何其他阳离子通道的可用信息 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： 特定的阳离子通道，使用来自蜡状芽孢杆菌的NaK通道，细菌Na+和K+传导 通道，其与CNG通道的孔同源，作为模型系统;和原核电压- 门控Na+通道。我们将结合使用晶体学和电生理学工具， 在结构和功能上表征这些通道。该研究提出了三个具体的 目标。第一个具体目标是在NaK中单价阳离子导电的结构和功能研究 频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， 也将为理解CNG中离子选择性的结构基础提供重要的见解 频道家族我们的第二个具体目标是研究NaK通道的二价阳离子阻断。这 研究将阐明CNG通道中二价阳离子阻断的潜在机制，这是一个 重要的生理意义，特别是视觉传导。第三，我们的目标是确定晶体 原核细胞电压门控Na+通道的离子传导孔的结构。这项研究不仅将 使我们能够阐明Na* 通道中离子选择性的结构基础，但也将阐明离子 Ca 2+通道的选择性过滤器与Na* 通道具有高度的序列同源性。