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Volatile Anesthetic Regulation of TASK Tandem Pore Potassium Channels

TASK 串联孔钾通道的挥发性麻醉调节

基本信息

批准号：
8320182
负责人：
Joseph F Cotten
金额：
$ 12.54万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8320182
关键词：
Acids Agonist Amino Acid Sequence Anesthesia procedures Anesthetics Breathing Bronchodilation Cells Chemosensitization Clinical Conscious Coupled Depressed mood Development Electrodes Electrophysiology (science)Exhibits Faculty General Hospitals General anesthetic drugs Halothane Health 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 Wakefulness Work Xenopus oocyte base cell type clinically relevant desflurane medical schools member mutant novel patch clamp programs receptor coupling receptor function reconstitution response sevoflurane skills voltage clamp

项目摘要

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（由申请方提供）：本提案描述了一项为期5年的培训计划，旨在培养挥发性麻醉机制方面的独立研究者。主要研究者是哈佛医学院麻醉系的教员，具有电生理学背景，他将获得足以领导自己独立研究项目的神经科学和药理学新知识和技能。工作将在马萨诸塞州总医院的Mallinckrodt药理学研究单位进行，重点是挥发性麻醉机制。我们的特定目的是检验挥发性麻醉剂通过抑制基础或激动剂介导的Galpha-q蛋白偶联受体（GqPCR）活性间接增强ASK-3功能的新假设。ASK-3串联孔钾通道是挥发性麻醉增强和pH和缺氧抑制的离子通道。ASK-3在中枢神经系统和外周组织中广泛表达，并在多种细胞类型中具有化学传感作用，包括参与呼吸调节的细胞。GqPCR激活也抑制了ASK-3功能。CNS中的GqPCR调节记忆、觉醒和意识，并且外周是平滑肌张力的重要调节剂。许多GqPCR的功能被挥发性麻醉剂抑制。为了验证我们的假设，我们将使用爪蟾卵母细胞的双电极电压钳或异源表达ASK-3通道和ml或m3 GqPCR和Galpha-q蛋白的Fischer大鼠甲状腺细胞的Ussing小室研究。我们也将采用离体膜片钳方法，以及几种分子生物学技术，包括RNA干扰和定点突变。长期目标：本项目将阐明挥发性麻醉药增强任务通道的分子机制。公共卫生相关性这项工作将有助于建立原则，指导开发不影响呼吸的更安全的麻醉药物，并进一步阐明这些药物诱导麻醉的机制。