Anesthesia is a clinical state of central nervous system (CMS) depression produced by th 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 CMS. 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.
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