SLO2 K+ CHANNELS: A MAJOR SYSTEM CONTROLLING EXCITABILITY IN THE BRAIN

我们相信，我们最近研究大脑神经元电特性的工作， 在理解钾通道如何控制神经元电活动的兴奋性方面取得了突破， 并可能对基础和临床神经科学产生重大影响。我们最近的研究表明 在许多神经元类型中，延迟外向钾传导的最大组成部分之一， 正常的生理学被忽视，是Na+激活的SLO 2（Slack）通道的产物。先前 对哺乳动物神经元中钾电导的研究可能忽略了这一重要组成部分， 外向电流，因为Na+通道阻滞剂TTX通常用于哺乳动物K+的研究 通道和TTX也消除SLO 2电流作为其阻断Na+进入的次要结果。 由于大多数先前对CNS神经元电特性的研究都忽略了大的SLO 2， 成分，我们建议显示其对几种脑中神经元电特性的贡献 这是一个突出表现的地区。这将使我们更深入地了解 确定神经元电活动，并可能揭示SLO 2通道作为有用的药理学靶点 用于控制癫痫和其它癫痫病症。因为SLO 2通道在细胞中的表达 在纹状体中，它们也可能是治疗帕金森病和治疗帕金森病的有用靶点。 抑郁症除了显示SLO 2通道对神经元电活动的贡献外， 兴奋性，我们也将揭示更多关于SLO 2 K+电流激活的机制。我们之前 发现SLO 2 K+电流是由Na+通过持续的内向钠通道进入激活的。 电导因此，我们将确定一个或多个携带这种蛋白的钠通道的遗传特性。 能够激活SLO 2通道的持续钠电流。我们还将研究功能 携带持续Na+电流的钠通道与SLO 2 Na+激活的钠通道之间的关系 渠道这些实验将在一个异源系统中进行，我们将在其中重建一个 SLO 2-钠通道偶联系统，并在实验中使用来自天然的单膜贴片 神经元，其中钠通道和SLO 2通道的功能相互作用可以在 钠进入仅限于贴片的限制条件。

We believe that our most recent work studying the electrical properties of neurons of the brain represents a breakthrough in understanding how potassium channels control the excitability of neuronal electrical activity, and may have a significant impact on both basic and clinical neuroscience. We have recently shown that one of the largest components of delayed outward potassium conductance in many neuronal types, during normal physiology has gone unnoticed and is the product of Na+-activated SLO2 (Slack) channels. Previous studies of potassium conductances in mammalian neurons may have overlooked this large component of outward current because the Na+ channel blocker TTX is typically used in studies of mammalian K+ channels and TTX also removes SLO2 currrents as a secondary consequence of its block of Na+ entry. Since most prior studies of the electrical properties of CNS neurons have overlooked the large SLO2 component, we propose to show its contribution to the electrical properties of neurons in several brain regions where it is prominently expressed. This will allow a more thorough understanding of the currents that determine neuronal electrical activity and may reveal SLO2 channels as useful pharmacological targets for the control of epilepsy and other seizure disorders. Because SLO2 channels are prominently expressed in the striatum they may also be a useful target in the treatment of Parkinson's Disease and in the treatment of depressive illness. In addition to showing the contribution of SLO2 channels to neuronal electrical excitability, we will also reveal more about the mechanism of SLO2 K+ current activation. We previously discovered that the SLO2 K+ current is activated by Na+ entry through a persistent inward sodium conductance. Thus, we will determine the genetic identity of one or more sodium channels that carry such a persistent sodium current capable of activating SLO2 channels. We will also investigate the functional relationships between sodium channels which carry a persistent Na+ current, and SLO2 Na+-activated channels. These experiments will be undertaken in a heterologous system where we will reconstitute a SLO2-sodium channel coupled system, and in experiments using single membrane patches from native neurons where the functional interactions of sodium channels and SLO2 channels can be studied under circumscribed conditions where sodium entry is limited to the patch.