Permeation and Gating of Inwardly-Rectifying Potassium Channels.

内向整流钾通道的渗透和门控。

• 批准号: 7667378
• 负责人: Harley T Kurata
• 金额: $ 7.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667378
• 关键词: Acidity; Action Potentials; Address; Amino Acid Substitution; Amino Acids; Arrhythmia; Bartter Disease; Binding; Binding Sites; Biochemical; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cations; Cell membrane; Complex; Computer Simulation; Coupling; Cytoplasmic Tail; Data; Defect; Dependence; Development; Diabetes Mellitus; Disease; Engineering; Epilepsy; Event; Gene Mutation; Goals; Grant; Heart; Intervention; Ion Channel; Ions; Lead; Ligand Binding; Ligands; Link; Location; Mammalian Cell; Maps; Measures; Mentors; Metabolism; Methodology; Methods; Modeling; Movement; Myocardial Contraction; Nucleotides; Pathway interactions; Phase; Phosphatidylinositol 4,5-Diphosphate; Phospholipids; Physiological; Polyamines; Positioning Attribute; Potassium; Potassium Channel; Property; Protein Family; Proteins; Regulation; Research; Resolution; Role; Shapes; Structure; Syndrome; System; Techniques; Vacuum; base; body system; design; in vivo; insight; inward rectifier potassium channel; neuromuscular; novel; protein complex; protein protein interaction; research study; tool; voltage

DESCRIPTION (provided by applicant): In the cardiovascular system, inwardly-rectifying potassium (Kir) channels are a critical component in the cardiac action potential, regulating both the shape and duration of the electrical events that underlie each heartbeat. A unique feature of this family of proteins is the range of cellular factors that regulate their activity, including inorganic cations, products of cellular metabolism, and changes in cellular acidity, and even properties of the cell membrane. Adding further diversity, the activity of Kir channels is regulated dynamically, from moment to moment, by voltage-dependent block by intracellular cations, and more tonically regulated by ligands that influence channel gating. Recent studies have begun to link genetic mutations that disrupt blockade or gating of specific Kir channels to various cardiac arrhythmias, vascular defects, and more severe disorders including Andersen's syndrome, Bartter's syndrome, and DEND (Diabetes with Epilepsy and Neuromuscular Defects), demonstrating a broad spectrum of physiological roles of this class of channels in many organ systems. The long-term goal of the proposed research is to understand the general and specific mechanisms underlying regulation of Kir channels by (1) their permeating ions, (2) soluble cellular factors that alter channel activity, and (3) interactions with other proteins. To tackle these questions, detailed experiments measuring the electrical activity of Kir channels will be combined with computer modeling, and powerful new biochemical techniques to introduce useful artificial/unnatural amino acids at specific locations in proteins. A detailed understanding of the fundamental mechanisms of Kir channel regulation will provide a basis for ultimately developing interventions to regulate disorders of electrical excitability in the heart, vasculature, and beyond.

描述（由申请人提供）： 在心血管系统中，内向整流钾 (Kir) 通道是心脏动作电位的关键组成部分，调节每次心跳背后的电事件的形状和持续时间。该蛋白质家族的一个独特特征是调节其活性的一系列细胞因子，包括无机阳离子、细胞代谢产物、细胞酸度的变化，甚至细胞膜的特性。进一步增加多样性，Kir 通道的活性通过细胞内阳离子的电压依赖性阻断而动态调节，并且通过影响通道门控的配体进行更多的调节调节。最近的研究已开始将破坏特定 Kir 通道封锁或门控的基因突变与各种心律失常、血管缺陷和更严重的疾病（包括安徒生综合征、巴特综合征和 DEND（伴有癫痫和神经肌肉缺陷的糖尿病））联系起来。此类通道在许多器官系统中的生理作用谱。拟议研究的长期目标是了解 Kir 通道调节的一般和具体机制：(1) 其渗透离子，(2) 改变通道活性的可溶性细胞因子，以及 (3) 与其他蛋白质的相互作用。为了解决这些问题，测量 Kir 通道电活动的详细实验将与计算机建模和强大的新生化技术相结合，以在蛋白质的特定位置引入有用的人工/非天然氨基酸。对 Kir 通道调节的基本机制的详细了解将为最终开发调节心脏、脉管系统等电兴奋性紊乱的干预措施奠定基础。