Background Potassium Channels as Anesthetic Targets

描述（由申请人提供）：麻醉是一种中枢神经系统（CMS）抑制的临床状态，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无知觉、记忆，也无反应。尽管有100多年的研究，全身麻醉发生的机制仍然未知。在过去的20-30年中确定的主要分子候选者是离子通道，其在CMS内的活性可以通过麻醉药物调节以产生麻醉状态。大量的工作调查的作用，配体门控离子通道，如GABAA，甘氨酸，神经元烟碱，谷氨酸和多巴胺能受体通道的麻醉机制已被报道，但未能令人信服地证明一个排他性的作用。选择性通过钾离子的离子通道- K通道-代表另一个可能的麻醉靶点。对钾通道的研究还不足以了解它们在麻醉机制中的作用。在钾离子通道的三个主要家族中，串联孔钾（Kap）通道家族是最近发现的。该家族的成员负责基线或背景K电流，其对于调节CNS中神经元的兴奋性是重要的。这个家族的主要成员通过的电流被挥发性全身麻醉药增强，为它们产生的CMS抑郁症提供了一个合理的解释。本文提供的初步数据表明，名为TRESK的K2 p通道被挥发性麻醉剂独特地激活，使其成为挥发性麻醉剂作用位点的非常有前途的候选者。在这项研究中，我们提出了对人类、小鼠和大鼠TRESK的药理学和表达模式的详细分析。我们还提出了基因沉默实验（使用RNA干扰），以改变TRESK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理解有可能导致麻醉药物或技术的改进。

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.