Volatile Anesthetic Regulation of TASK Tandem Pore Potassium Channels

TASK 串联孔钾通道的挥发性麻醉调节

• 批准号: 7922796
• 负责人: Joseph F Cotten
• 金额: $ 10.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922796
• 关键词: Acids; Agonist; Amino Acid Sequence; Anesthesia procedures; Anesthetics; Breathing; Bronchodilation; Cells; Chemosensitization; Clinical; Conscious; Coupled; Development; Electrodes; Electrophysiology (science); Exhibits; Faculty; General Anesthesia; General Hospitals; General anesthetic drugs; Halothane; Hypoxia; Inbred F344 Rats; Ion Channel; Isoflurane; Knowledge; Lead; Mammalian Cell; Mediating; Memory; Methods; Molecular; Molecular Biology Techniques; Muscarinics; Muscle Tonus; Nervous system structure; Neuraxis; Neurosciences; Peripheral; Pharmaceutical Preparations; Pharmacology; Potassium; Potassium Channel; Principal Investigator; Program Development; Proteins; Public Health; RNA Interference; Receptor Activation; Receptor Inhibition; Regulation; Research; Research Personnel; Resistance; Role; Signaling Protein; Site; Site-Directed Mutagenesis; Smooth Muscle; Testing; Thyroid Gland; Tissues; Training Programs; Vasodilation; Wakefulness; Work; Xenopus oocyte; base; cell type; clinically relevant; depressed; desflurane; medical schools; member; mutant; novel; patch clamp; programs; receptor coupling; receptor function; reconstitution; response; sevoflurane; skills; voltage clamp

This proposal describes a 5-year training program for the development of an independent investigator in volatile anesthetic mechanisms. The principal investigator is a faculty member in the Department of Anesthesia, Harvard Medical School, with a background in electrophysiology,who will acquire new knowledge and skills in neuroscience and pharmacology sufficient to lead his own independent research program. Work will be conducted in the Mallinckrodt Pharmacology Research Unit at Massachussets General Hospital which focuses on volatile anesthetic mechanisms. ; Our SPECIFIC AIMS wil test the novel hypothesis that volatile anesthetics potentiate TASK-3 function indirectly by inhibition of basal or agonst-mediated Galpha-q protein coupled receptor (GqPCR) activity. The TASK-3 tandem pore potassium channel is a volatile anesthetic-potentiated and pH- and hypoxia-inhibited ion channel. TASK-3 is widely expressed in the central nervous system and in peripheral tissue and has a role in chemosensing in a variety of cell types, including those involved in regulation of breathing. TASK-3 function is also inhibited by GqPCR activation. GqPCRs in the CNS regulate memory, wakefulness, and consciousness and peripherally are important regulators of smooth muscle tone. The function of many GqPCRs are inhibited by volatile anesthetics. To test our hypothesis we will use two-electrode voltage clamp of Xenopus oocytes or Ussing Chamber studies of Fischer Rat Thyroid cells heterologously expressing TASK-3 channels and ml or m3 GqPCRs and Galpha-q protein. We will also employ the excised patch-clamp method, and several molecular biology techniques including RNA interference and site-directed mutagenesis. LONG TERM GOALS: This project will clairfy the molecular mechanism by which volatile anesthetics potentiate TASK channels. RELEVANCE TO PUBLIC HEALTH: This work will help establish principles to guide development of safer anesthetic drugs that do not effect breathing and further elucidate the mechanism by which these drugs induce anesthesia. i

该提案描述了一个为期5年的培训计划，以培养一名独立的调查员， 挥发性麻醉机制首席研究员是一名教员在系 麻醉，哈佛医学院，在电生理学的背景，谁将获得新的 在神经科学和药理学方面的知识和技能足以领导他自己的独立研究 程序.工作将在马萨诸塞州的马林克罗特药理学研究室进行 重点研究挥发性麻醉机制的综合医院。; 我们的具体目标是检验挥发性麻醉剂增强任务-3功能的新假设 间接通过抑制基础或激动剂介导的Galpha-q蛋白偶联受体（GqPCR）活性。的 ASK-3串联孔钾通道是一种挥发性麻醉增强和pH和缺氧抑制的钾通道 离子通道ASK-3在中枢神经系统和外周组织中广泛表达，并具有与神经系统相关的功能。 在各种细胞类型中的化学传感中起作用，包括参与呼吸调节的细胞。任务-3 功能也受到GqPCR激活的抑制。CNS中的GqPCR调节记忆、觉醒和 意识和外周是平滑肌张力的重要调节器。多元函数 GqPCR被挥发性麻醉剂抑制。为了验证我们的假设，我们将使用双电极电压 爪蟾卵母细胞钳夹法或Ussing小室法研究Fischer大鼠甲状腺细胞的异源性 表达ASK-3通道和ml或m3 GqPCR和Galpha-q蛋白。我们也会雇佣那些 膜片钳方法以及RNA干扰和定点等多种分子生物学技术 诱变长期目标：该项目将阐明挥发性化合物的分子机制， 麻醉剂增强了任务通道。与公共卫生的关系：这项工作将有助于建立 指导开发不影响呼吸的更安全麻醉药物的原则，并进一步阐明 这些药物诱导麻醉的机制。我