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

K2P 结构、功能和调节的遗传和化学生物学研究

• 批准号: 9884602
• 负责人: DANIEL L MINOR
• 金额: $ 46.87万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884602
• 关键词: Address; Affect; Amlodipine; Anesthetics; Antibodies; Architecture; Arrhythmia; Behavior; Biochemical; Biological; Biophysics; Brain; C-terminal; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Cognition; Complex; Conflict (Psychology); Development; Drug Targeting; Drug usage; Electrophysiology (science); Elements; Epilepsy; Family; Family member; Fluoxetine; Funding; Genes; Genetic; Goals; Heart; Human; Hypertension; In Vitro; Investigation; Ion Channel; Knowledge; Laboratories; Lipids; Measurement; Mechanics; Membrane Proteins; Mental Depression; Metabolic; Methods; Modality; Molecular; Molecular Conformation; Mood Disorders; Moods; Mutagenesis; Nature; Nervous system structure; Neurons; Orphan; Pain; Pharmacology; Physiology; Play; Potassium; Potassium Channel; Property; Protons; Reagent; Rest; Role; Series; Shapes; Signal Transduction; Site; Spottings; Stimulus; Stroke; Structure; Subgroup; Tail; Temperature; Testing; Therapeutic Agents; Work; chronic pain; crosslink; dimer; experimental study; extracellular; genetic selection; human disease; in vivo; inhibitor/antagonist; interdisciplinary approach; mechanical force; mutant; novel; novel therapeutics; potassium channel protein TREK-1; pressure; public health relevance; response; sensory system; small molecule; targeted treatment; tool

 DESCRIPTION (provided by applicant): 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 are 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 of the well-established approaches for modulator development that require purified material. 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, and electrophysiological measurements and genetic selections to identify, dissect, and characterize the core elements that control K2P function and to define and characterize new small molecules that 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 means to find 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.

 描述（由适用提供）：该项目的长期目标是对控制K2P钾通道功能的基本机制的理解，并识别，开发和表征K2P家族的小分子，离子通道调节剂。 K2P是钾选择性通道的不同家族，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对包括pH变化，温度和机械力的各种刺激做出了反应。尽管K2P在神经和心血管系统中具有完善的角色，并且暗示着疼痛，麻醉反应，热效和情绪，但它们是最不受欢迎的钾通道类。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访问，并且调节会带来心脏和大脑中令人兴奋的细胞的特性的快速变化。但是，作为膜蛋白，它们也居住在许多需要纯化材料的调节剂开发方法之外。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功能连接的能力存在差距。我们正在采用一种多学科方法，其中包括生物物理，结构和电生理测量和遗传选择，以识别，解剖和表征控制K2P功能的核心元素，并定义和表征控制K2P活性的新的小分子。定义控制K2P活性并发现新的K2P调节器的分子机制应提供关键框架和必要的工具，以了解K2PS的功能。由于它们在人类生理学中的重要作用，K2P是治疗慢性疼痛，中风和抑郁症的药物的靶标。这是对K2P的功能和方法的理解，而影响通道功能的小分子不仅应提供有力的工具来解剖K2P机制，还应有助于开发新的治疗剂来为一系列人类疾病开发。