Background Potassium Channels as Anesthetic Targets

描述（由申请人提供）：对细胞的完整理解 挥发性麻醉药产生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 对于这些代理商。许多研究提供了证据， γ-氨基丁酸能和谷氨酸能受体系统在介导抗肿瘤作用中的作用 挥发性麻醉剂另一种离子电流，背景钾 电流（也称为静息或基线K+电流）最近被 确定为挥发性麻醉剂作用的合理部位。这笔赠款是一个 继续六年前开始的研究，以阐明背景的作用， 正常生理状态和麻醉状态下的K+电流。一个新 具有两个串联成孔序列的K+通道的结构类别是 负责背景K+电流。我们克隆了这个家族的成员， 证明了它们在中枢神经系统中的存在，并研究了它们的 挥发性麻醉剂的激活浓度与临床 范围其他研究者已经记录了背景K+通道的活动 在体内，并证明对神经元系统的抑制作用， 通过挥发性麻醉剂增强。这项补助金的目的有三：（1） 表征剩余的功能和麻醉敏感性 这类离子通道结构中尚未发现的成员;（2）研究在 细胞水平上串联孔钾通道的组织分布，以获得 了解它们的正常生理功能;（3）识别分子 负责挥发性麻醉剂作用的区域。通过这些实验，我们 我希望对背景K+通道有更全面的了解 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.