Genetic and chemical biological studies of K2P structure, function, andmodulation

K2P 结构、功能和调节的遗传和化学生物学研究

• 批准号: 10444595
• 负责人: DANIEL L MINOR
• 金额: $ 78.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444595
• 关键词: Address; Affect; Amines; Anesthetics; Arrhythmia; Behavior; Binding; Binding Sites; Biochemical; Biological; Biology; Biophysics; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Complex; Development; Disulfides; Drug Targeting; Drug usage; Electrophysiology (science); Elements; Engineering; Environment; Epilepsy; Family; Family member; Foundations; Genes; Genetic; Goals; Heart; Human; Hypertension; Investigation; Ion Channel; Ions; Knowledge; Lipid Binding; Lipids; Maps; Mass Spectrum Analysis; Measurement; Mechanics; Membrane; Membrane Proteins; Mental Depression; Modality; Modeling; Molecular; Molecular Conformation; Mood Disorders; Moods; Mutagenesis; Nature; Nervous system structure; Neurons; Pain; Pharmacology; Physiology; Play; Potassium; Potassium Channel; Process; Property; Protein Engineering; Reagent; Role; Ruthenium; SF1; Signal Transduction; Site; Stimulus; Stroke; Structure; Temperature; Testing; Therapeutic Agents; Work; X-Ray Crystallography; chronic pain management; computer studies; design; dimer; efficacious treatment; extracellular; human disease; in vivo; insight; interdisciplinary approach; mechanical force; member; molecular dynamics; mutant; nanodisk; nanomolar; novel; novel therapeutics; particle; potassium channel protein TREK-1; potassium ion; preference; pressure; response; sensory system; simulation; small molecule; targeted treatment; tool

Project Summary The long-term goals of this project are to develop an understanding of the fundamental mechanisms that control the function of K2P potassium channels and to identify, develop, and characterize small molecule, ion channel modulators for the K2P family. K2Ps are a diverse family of potassium-selective channels that are responsible for background ‘leak’ currents. These currents are pivotal in modulating the excitability of neurons. K2Ps respond to varied stimuli that include pH changes, temperature, and mechanical force. Although K2Ps have well-established roles in the nervous and cardiovascular systems and are implicated in pain, anesthetic responses, thermosensation, and mood, they remain the least well-understood potassium channel class. Ion channels are coveted drug targets. As membrane proteins, they are readily accessible to extracellular compounds and their modulation brings about rapid changes in the properties of excitable cells in the heart and brain. However, as membrane proteins, they also reside beyond many well-established approaches for modulator development. Consequently, many channels, including those in the K2P family, lack significant pharmacologies. This problem leads to a gap in our ability to connect ion channel genes with in vivo function. We are pursuing a multidisciplinary approach that includes biophysical, structural, computational, and electrophysiological measurements and chemical biology approaches to identify, dissect, and characterize the core elements that control K2P function and to define and characterize new small molecules that can control K2P activity. Defining the molecular mechanisms that control K2p activity and uncovering new K2P modulators should provide the key framework and necessary tools for understanding how K2Ps function. Because of their important roles in human physiology, K2Ps are targets for drugs for the treatment of chronic pain, stroke, and depression. Thus, developing an understanding of how K2Ps function and small molecules that affect channel function should not only provide powerful tools for dissecting K2P mechanism but should aid in the development of new therapeutic agents for a range of human diseases.

项目摘要 该项目的长期目标是建立对控制的基本机制的理解 K2P钾通道的功能，并识别，发展和表征小分子，离子通道 K2P家族的调节器。 K2P是钾选择性渠道的潜水家族，负责 背景“泄漏”电流。这些电流在调节神经元的兴奋中至关重要。 K2P回应 各种刺激，包括pH变化，温度和机械力。虽然K2P已建立了 在神经和心血管系统中的作用，暗示疼痛，麻醉反应， 热敏度和情绪仍然是最不理解的钾通道类。离子通道是 令人垂涎的药物靶标。作为膜蛋白，它们很容易被细胞外化合物及其 调节带来了心脏和大脑中令人兴奋的细胞的特性的快速变化。但是，如 膜蛋白，它们还居住在许多建立调节剂开发的方法之外。 因此，许多渠道，包括K2P家族中的渠道，缺乏重要的药物学。这个问题 导致我们将离子通道基因与体内函数连接的能力差距。我们正在追求 多学科方法，包括生物物理，结构，计算和电生理学 测量和化学生物学方法，以识别，剖析和表征核心要素 控制K2P功能并定义和表征可以控制K2P活性的新的小分子。定义 控制K2P活性和发现新的K2P调制器的分子机制应提供钥匙 框架和必要的工具，以了解K2PS的功能。因为它们在人类中的重要角色 生理学，K2P是用于治疗慢性疼痛，中风和抑郁症的药物的靶标。那，正在发展 了解K2PS功能和影响通道功能的小分子的理解不仅应提供 剖析K2P机制的强大工具，但应有助于开发新的治疗剂 人类疾病范围。