Background Potassium Channels as Anesthetic Targets

描述(申请人提供)：麻醉是中枢神经系统(CMS)抑郁的一种临床状态，由各种药物的全身给药产生。在麻醉状态下，病人对手术的有害刺激既没有知觉，也没有记忆，也没有反应。尽管进行了100多年的研究，但全身麻醉发生的机制(S)仍不清楚。在过去20-30年中确定的主要候选分子是离子通道，其在CMS内的活动可能被麻醉药物调节以产生麻醉状态。已有大量工作报道了配体门控离子通道，如GABAA、甘氨酸、神经元烟碱、谷氨酸和5-羟色胺能受体通道在麻醉机制中的作用，但未能令人信服地证明其具有排他性作用。选择性地通过钾离子的离子通道--K通道--是另一个看似合理的麻醉剂靶点。对K通道的研究还不充分，无法了解它们在麻醉机制中的作用。在K通道的三个主要家族中，串联孔K(Kap)通道家族是最新发现的。这个家族的成员负责基线或背景K电流，这对调节中枢神经系统神经元的兴奋性很重要。这个家族的主要成员传递的电流被挥发性全麻药增强，为他们产生的CMS抑郁提供了一个可信的解释。这里提供的初步数据显示，名为Tresk的K2p通道唯一地被挥发性麻醉剂激活，使其成为非常有希望的挥发性麻醉作用部位的候选者。在这项资助中，我们建议对人、小鼠和大鼠Tresk的药理和表达模式进行详细分析。我们还提出了基因沉默实验(使用RNA干扰)来改变Tresk的表达，以确定其参与整个动物对麻醉剂的反应。对麻醉的基本机制的了解有可能导致改进麻醉药物或技术。

DESCRIPTION (provided by applicant): Anesthesia is a clinical state of central nervous system (CMS) depression produced by the systemic administration of a variety of drugs. Under anesthesia a patient has neither awareness, remembrance, nor response to the noxious stimulation of surgery. Despite more that 100 years of investigation, the mechanism(s) by which general anesthesia occurs remains unknown. The principal molecular candidates identified over the last 20-30 years are ion channels whose activities within the CMS may be modulated by anesthetic drugs to produce the anesthetic state. Substantial work investigating the role of ligand-gated ion channels such as GABAA, glycine, neuronal nicotinic, glutamate and serotonergic receptor channels in anesthesia mechanisms has been reported but has failed to convincingly prove an exclusive role. Ion channels that selectively pass potassium ions - K channels - represent another plausible anesthetic target. Insufficient investigation has taken place on K channels to understand their role in anesthetic mechanisms. Of the three main families of K channels, the tandem pore K (Kap) channel family has been the most recently discovered. Members of this family are responsible for baseline or background K currents that are important for regulating the excitability of neurons in the CNS. Currents passed by the major members of this family are potentiated by volatile general anesthetics, providing a plausible explanation for the CMS depression they produce. Preliminary data presented here show that the K2p channel named TRESK is uniquely activated by volatile anesthetics, making it a highly promising candidate for a site of volatile anesthetic action. In this grant we propose a detailed analysis of the pharmacology and expression pattern of human, mouse and rat TRESK. We also propose gene silencing experiments (using RNA interference) to alter TRESK expression in order to determine its involvement in the whole animal response to anesthetics. An understanding of the basic mechanisms underlying anesthesia has the potential to lead to improved anesthetic drugs or techniques.