Background Potassium Channels as Anesthetic Targets

描述(由申请人提供)：对手机的完整理解 以及由挥发性麻醉剂产生的麻醉状态的分子基础 仍然难以捉摸。离子通道蛋白提供了最有可能的分子靶点 对这些特工来说。许多研究已经提供了证据表明， GABA能和谷氨酸能受体系统在介导阿片受体中的作用 挥发性麻醉剂。另一种离子流，背景钾 电流(也称为静息或基线K+电流)最近 被确认为易挥发麻醉作用的合理场所。这笔赠款是一笔 六年前开始的继续研究，以阐明背景的作用 正常生理状态和麻醉状态下的K+电流。一种新的 具有两个串联成孔序列的K+通道的结构类别为 负责本底K+电流。我们克隆了这个家族的成员， 证明了它们存在于中枢神经系统，并研究了它们的 挥发性麻醉剂在与临床重叠的浓度下的激活 射程。其他研究人员记录了背景K+通道的活动 在体内，并证明对神经系统的抑制作用 由挥发性麻醉剂增强。这笔拨款的目的有三个：(1) 描述剩余部分的功能和麻醉敏感性 这种离子通道结构类别中未被发现的成员；(2)研究 在细胞水平上获得串联孔K+通道的组织分布 深入了解它们的正常生理功能；(3)鉴定分子 负责挥发性麻醉作用的区域。通过这些实验，我们 预计将出现对背景K+通道的更全面的了解 并阐明了它们在调节麻醉状态中的作用。

DESCRIPTION (provided by applicant): A complete understanding of the cellular and molecular basis of the anesthetized state produced by volatile anesthestics remains elusive. Ion channel proteins provide the most likely molecular targets for these agents. Many studies have provided evidence for the involvement of GABAergic and glutamatergic receptor systems in mediating the action of volatile anesthetics. An additional type of ionic current, background potassium currents(also known as resting or baseline K+ currents) have recently been identified as plausible sites for volatile anesthetic action. This grant is a continuation of studies begun six years ago to elucidate the role of background K+ currents in normal physiology and in the anesthetized state. A new structural class of K+ channels with two pore-forming sequences in tandem are responsible for background K+ currents. We have cloned members of this family, demonstrated their presence in the central nervous system and studied their activation by volatile anesthetics at concentrations overlapping the clinical range. Other investigators have recorded the activity of background K+ channels in vivo and demonstrated inhibitory effects on neuronal systems that are enhanced by volatile anesthetics. The aims of this grant are threefold: (1) to characterize the function and anesthetic sensitivity of the remaining undiscovered members of this structural class of ion channels; (2) to study at the cellular level the tissue distribution of tandem pore K+ channels to gain insight into their normal physiologic function; (3) to identify the molecular domains responsible for volatile anesthetic action. With these experiments we expect that a more complete understanding of background K+ channels will emerge and their role in mediating the anesthetic state clarified.