Channels with KCNE Subunits: Conformational Dynamics

具有 KCNE 子单元的通道：构象动力学

• 批准号: 8582069
• 负责人: Steve A N Goldstein
• 金额: $ 37.69万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582069
• 关键词: Address; Biology; Cardiac; Cardiovascular system; Cells; Colon; Conflict (Psychology); Data; Dependence; Diagnosis; Disease; Ear; Energy Transfer; Environment; Exercise; Fluorescence; Functional disorder; Goals; Health; Heart; Heart Diseases; Human; Human Activities; Inherited; Investigation; Ion Channel; Ions; Kinetics; Knowledge; Lanthanoid Series Elements; Learning; Link; Locales; Location; Maintenance; Measurement; Measures; Medicine; Methods; Microscopy; Mink; Modeling; Movement; Nervous system structure; Optics; Organ; Outcome; Peptides; Persons; Pharmacologic Substance; Pharmacology; Phase; Photobleaching; Physiological; Physiology; Potassium; Process; Property; Proteins; Regulation; Reporting; Research; Rest; Scheme; Site; Structural Models; Structure; Techniques; Testing; Time; Ursidae Family; Variant; Voltage-Gated Potassium Channel; Wit; Work; base; computerized tools; disorder risk; heart function; improved; in vivo; insight; muscular system; operation; response; sensor; single molecule; stoichiometry; tool; voltage

DESCRIPTION (provided by applicant): The goal of this work is to determine how voltage-gated potassium (Kv) channels are controlled by KCNE subunits. Also called MinK-related peptides (MiRPs), these single-pass transmembrane accessory subunits merit investigation because they are required for normal function of the heart and other organs that depend on Kv channels. MiRPs exert their powerful effects by assembly with Kv channel pore-forming subunits and thereby direct location and level, voltage-sensitivity, time- dependence, unitary conductance, ion selectivity, and response to regulators and pharmaceuticals. Identifying and studying MiRPs has advanced diagnosis and treatment of cardiac disease. The significance of this application is two-fold. First, we have learned a great deal about what MiRPs do in the heart over the last decade but not yet how they do it. Second, tools are now available to delineate conformational dynamics, that is, the mechanistic basis for protein operation in real-time. Here, powerful optical, electrophysiological and modeling techniques are brought to bear on channels as they form in cells, a capability unimaginable just a decade ago. The result is no less than this: we can now answer basic, outstanding questions in human physiology and disease. The three aims focus on operation of two important channels formed by the same pore-forming Kv subunit (Kv7.1 = KCNQ1 = Q1) and two different MiRPs (MinK = E1 and MiRP2 = E3). The study addresses questions at the core of physiology. To wit: why does IKs (Q1 + E1) in the heart and ear respond slowly to voltage? How does IK (Q1 + E3) found in heart and colon react instantaneously to voltage? These normal functions are disrupted by inherited differences and acquired disease. More basically, the study can reveal key principles of operation of voltage sensors and gates and the impact of accessory subunits; these insights have relevance throughout the body.

描述（由申请人提供）：这项工作的目标是确定电压门控钾（Kv）通道如何由KCNE亚基控制。也被称为MinK相关肽（MiRPs），这些单程跨膜辅助亚基值得研究，因为它们是心脏和其他依赖Kv通道的器官的正常功能所必需的。MiRP通过与Kv通道孔形成亚基组装发挥其强大的作用，从而指导位置和水平、电压敏感性、时间依赖性、单位电导、离子选择性以及对调节剂和药物的响应。识别和研究MiRPs对心脏疾病的诊断和治疗具有重要意义。这项申请的意义有两方面。首先，在过去的十年里，我们已经了解了很多关于MiRPs在心脏中的作用，但还没有了解它们是如何做到这一点的;其次，现在可以使用工具来描述构象动力学，即实时蛋白质操作的机制基础。在这里，强大的光学，电生理和建模技术被用于在细胞中形成通道，这在十年前是不可想象的。其结果是：我们现在可以回答人类生理学和疾病中基本的、悬而未决的问题。这三个目标集中于由相同的成孔Kv亚基（Kv7.1 = KCNQ 1 = Q1）和两个不同的MiRP（MinK = E1和MiRP 2 = E3）形成的两个重要通道的操作。这项研究解决了生理学的核心问题。也就是说：为什么心脏和耳朵中的IKs（Q1 + E1）对电压反应缓慢？在心脏和结肠中发现的IK（Q1 + E3）如何对电压做出即时反应？这些正常功能被遗传差异和后天疾病破坏。更基本的是，这项研究可以揭示电压传感器和门的关键操作原理以及附属亚基的影响;这些见解与整个身体相关。