BACKGROUND POTASSIUM CHANNELS AS ANESTHETIC TARGETS

钾离子通道作为麻醉目标的背景

• 批准号: 2686327
• 负责人: CHARLES S YOST
• 金额: $ 18.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2686327
• 关键词: Xenopus oocyte; anesthetics; computer assisted sequence analysis; electrophysiology; fluorescent in situ hybridization; gene expression; general anesthesia; granule cell; halothane; in situ hybridization; isoflurane; molecular cloning; neural inhibition; neuropharmacology; northern blottings; potassium channel; site directed mutagenesis; voltage /patch clamp

Although it has been known for more than 150 years that volatile anesthetics produce central nervous system (CNS) depression in numerous species, the basic mechanisms underlying anesthetic action are not yet understood. We hypothesize that volatile anesthetics induce neuronal inhibition primarily by activating a discrete class of potassium (K+) channels responsible for background currents (also known as baseline or leak currents). We have shown that in neurons of the mollusc Aplysia californica, volatile anesthetics increase the open probability of an outwardly rectifying background K+ channel (S-K channel), resulting in neuronal hyperpolarization and silencing of spontaneous action potentials. A recently discovered class of K+ channels, distinguished by having two putative pore-forming sequences tandemly arrayed within their primary amino acid sequence, appears to mediate background currents. We found that the function of the prototypic member of this family, a yeast outwardly rectifying background channel (TOK1) is potentiated by volatile anesthetics. TOK1 potentiation obeys the rank order of clinical potency halothane greater than isoflurane greater than desflurane), overlaps the clinical range, does not occur with non- anesthetics and is stereospecific [S(+) greater than R(-)-isoflurane]. We also have preliminary evidence for the presence of volatile anesthetic-stimulated baseline K+ channels in mammalian brain (rat cerebellar granule cells). We now propose the continuation of these studies by cloning and expressing new members of the tandem pore K+ channel family for studies of their sensitivity to volatile anesthetics. The proposed studies are important from three perspectives: 1) they have the potential for elucidating a molecular mechanism of volatile anesthetic action; 2) they will lead to a greater understanding of the role of background channels in CNS activity; 3) they may provide targets for the development of more specific anesthetic agents.

尽管150多年前人们就知道它不稳定