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: 7681262
• 负责人: Joseph F Cotten
• 金额: $ 13.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681262
• 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; 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; public health relevance; receptor coupling; receptor function; reconstitution; response; sevoflurane; skills; voltage clamp

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，以开发独立研究者的挥发性麻醉机制。首席研究员是哈佛医学院麻醉系的教职员工，具有电生理学背景，他们将获得足以领导自己独立研究计划的神经科学和药理学领域的新知识和技能。马萨诸塞州综合医院的Mallinckrodt药理学研究部门将进行工作，该研究专注于挥发性麻醉机制。我们的特定目的WIL检验了一种新的假设，即通过抑制基底或Agonst介导的Galpha-Q蛋白偶联受体（GQPCR）活性，挥发性麻醉药可增强任务3的功能。任务3串联孔钾通道是一种挥发性麻醉仪且抑制pH和缺氧的离子通道。 Task-3在中枢神经系统和周围组织中广泛表达，并且在多种细胞类型的化学传感中起作用，包括参与调节呼吸的细胞类型。 Task-3功能还被GQPCR激活抑制。中枢神经系统中的GQPCR调节记忆，清醒，意识和外围是平滑肌音调的重要调节因子。许多GQPCR的功能受到挥发性麻醉剂的抑制。为了检验我们的假设，我们将使用双电极卵母细胞的两种电压电压夹，或对Fischer大鼠甲状腺甲状腺细胞的使用室研究异源表达任务-3通道以及ML或M3 GQPCRS和Galpha-Q蛋白。我们还将采用切除的斑块钳方法，以及几种分子生物学技术，包括RNA干扰和定向诱变。长期目标：该项目将使挥发性麻醉剂增强任务渠道的分子机制。公共卫生相关性这项工作将有助于建立原则，以指导开发不影响呼吸并进一步阐明这些药物引起麻醉的机制的更安全的麻醉药物。