BACKGROUND POTASSIUM CHANNELS AS ANESTHETIC TARGETS

钾离子通道作为麻醉目标的背景

• 批准号: 6019491
• 负责人: CHARLES S YOST
• 金额: $ 22.78万
• 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/6019491
• 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多年来人们都知道 麻醉剂产生中枢神经系统（CNS）抑制， 物种，麻醉作用的基本机制还没有 明白 我们假设挥发性麻醉剂诱导神经元 抑制主要通过激活一个离散类钾（K+） 负责背景电流的通道（也称为基线或 漏电流）。我们已经证明，在软体动物Aaplasia的神经元中， 在加利福尼亚州，挥发性麻醉剂增加了开放的概率， 外向整流背景K+通道（S-K通道），导致 神经元超极化和自发活动的沉默 潜力 最近发现的一类K+通道， 通过使两个假定的成孔序列串联排列在 它们的主要氨基酸序列，似乎介导背景 水流 我们发现这个原型成员的功能 家族，酵母向外整流背景通道（TOK 1）， 通过挥发性麻醉剂增强。 TOK 1增强遵循等级 临床效力的顺序氟烷大于异氟烷大于 地氟烷），与临床范围重叠，不发生非- 麻醉剂和立体特异性[S（+）大于R（-）-异氟烷]。 我们也有初步证据表明 麻醉刺激的哺乳动物脑（大鼠）中的基线K+通道 小脑颗粒细胞）。 我们现在建议继续这些 通过克隆和表达串联孔K+的新成员的研究 通道家族，用于研究其对挥发性麻醉剂的敏感性。 建议的研究从三个方面来看是重要的：1）他们有 潜在的阐明挥发性的分子机制， 2）他们将导致更好地了解麻醉作用; 背景通道在中枢神经系统活动中的作用; 3）它们可以提供靶点 用于开发更特异的麻醉剂。