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

该提案描述了一项为期5年的培训计划，以开发独立研究者 挥发性麻醉机制。首席调查员是部门的教职员工 麻醉，哈佛医学院，具有电生理学背景，他将获得新的 神经科学和药理学方面的知识和技能足以领导自己的独立研究 程序。工作将在马萨诸塞州的Mallinckrodt药理学研究部门进行 综合医院专注于挥发性麻醉机制。 ; 我们的具体目的将检验一个新的假设，即挥发性麻醉剂增强了任务-3功能 通过抑制基础或Agonst介导的Galpha-Q蛋白偶联受体（GQPCR）活性间接地。这 Task-3串联孔钾通道是一种挥发性麻醉症，抑制pH和缺氧 离子通道。任务3在中枢神经系统和周围组织中广泛表达，具有 在各种细胞类型中的化学相变中的作用，包括参与呼吸调节的细胞。任务3 GQPCR激活也抑制了功能。中枢神经系统中的GQPCR调节记忆，清醒和 意识和外围是平滑肌音调的重要调节因子。许多功能 GQPCR被挥发性麻醉剂抑制。为了检验我们的假设，我们将使用两电极电压 异植型卵母细胞的夹具或Fischer大鼠甲状腺细胞的室内研究 表达任务3通道以及ML或M3 GQPCR和Galpha-Q蛋白。我们还将采用切除的 斑块钳法和几种分子生物学技术，包括RNA干扰和位置定向 诱变。长期目标：这个项目将使挥发性的分子机制保持紧张 麻醉剂增强任务渠道。与公共卫生有关：这项工作将有助于建立 指导不影响呼吸并进一步阐明的安全麻醉药物开发的原则 这些药物诱导麻醉的机制。我