Channels with KCNE Subunits: Conformational Dynamics

具有 KCNE 子单元的通道：构象动力学

• 批准号: 8301562
• 负责人: Steve A N Goldstein
• 金额: $ 36.62万
• 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/8301562
• 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 KCNE 亚基如何控制电压门控钾 (Kv) 通道。这些单次跨膜辅助亚基也称为 MinK 相关肽 (MiRP)，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 通道成孔亚基组装来发挥其强大的作用，从而指导位置和水平、电压敏感性、时间依赖性、单一电导、离子选择性以及对调节剂和药物的响应。识别和研究 MiRP 可以促进心脏病的诊断和治疗。该应用程序的意义有两个。首先，在过去的十年里，我们对 MiRP 在心脏中的作用有了很多了解，但还不清楚它们是如何做到的。其次，现在可以使用工具来描述构象动力学，即蛋白质实时操作的机制基础。在这里，强大的光学、电生理学和建模技术对细胞中形成的通道产生影响，这在十年前是不可想象的。结果不亚于这样：我们现在可以回答人类生理学和疾病中基本的、突出的问题。这三个目标侧重于由相同的成孔 Kv 亚基 (Kv7.1 = KCNQ1 = Q1) 和两个不同的 MiRP (MinK = E1 和 MiRP2 = E3) 形成的两个重要通道的操作。该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 IK（Q1 + E1）对电压反应缓慢？心脏和结肠中的 IK (Q1 + E3) 对电压有何瞬时反应？这些正常功能会因遗传差异和后天疾病而受到破坏。更重要的是，该研究可以揭示电压传感器和门的关键工作原理以及辅助子单元的影响；这些见解与整个机构都有关联。