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）：这项工作的目的是确定电压门控钾（KV）通道如何由KCNE亚基控制。这些单人跨膜附件亚基也称为Mink相关的肽（MIRP），因为它们是依赖KV通道的正常功能和其他器官的正常功能所必需的。 Mirps通过与KV通道孔形成亚基的组装发挥强大的作用，从而直接位置和水平，电压敏感性，时间依赖性，统一电导，离子选择性以及对调节剂和药品的响应。识别和研究MIRP具有心脏病的晚期诊断和治疗。该应用的意义是两个倍。首先，我们在过去的十年中了解了Mirps在心中的工作很多，但尚未做到这一点。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械基础。在这里，强大的光学，电生理和建模技术在细胞中形成时会在通道上携带，这是十年前无法想象的能力。结果不少：我们现在可以回答人类生理和疾病中的基本，杰出的问题。这三个目的集中于由相同的孔kV亚基（KV7.1 = kCnq1 = q1）和两个不同的miRP（mink = e1 and mirp2 = e3）形成的两个重要通道的操作。该研究以生理核心解决了问题。机智：为什么IK​​S（Q1 + E1）心脏和耳朵在慢慢反应电压？ IK（Q1 + E3）在心脏和结肠中如何立即反应电压？这些正常功能受到遗传差异和获得性疾病的破坏。基本上，该研究可以揭示电压传感器和门的运行的关键原理以及附件亚基的影响；这些见解在整个身体中具有相关性。