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

SLO2 K 通道：控制大脑兴奋性的主要系统

• 批准号: 7782115
• 负责人: LAWRENCE B SALKOFF
• 金额: $ 40.49万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782115
• 关键词: Antibodies; Attention; Brain; Brain region; Cells; Clinical; Co-Immunoprecipitations; Corpus striatum structure; Coupled; Coupling; Cytoplasm; Development; Electrostatics; Epilepsy; Excision; Genes; Genetic Identity; Grant; Membrane; Molecular; Neurons; Neurosciences; Oocytes; Outcome; Parkinson Disease; Physiological; Physiology; Play; Potassium; Potassium Channel; Relative (related person); Rodent; Role; Small Interfering RNA; Sodium; Sodium Channel; System; Techniques; Time; Work; cell type; channel blockers; depressive symptoms; electrical property; neuronal excitability; olfactory bulb; reconstitution; research study

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.

我们相信，我们最近研究大脑神经元电特性的工作代表了 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。我们最近表明 许多神经元类型中延迟向外钾电导的最大组成部分之一，在 正常生理机能未被注意到，它是 Na+ 激活的 SLO2 (Slack) 通道的产物。以前的 对哺乳动物神经元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 还消除了 SLO2 电流，这是其阻止 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 SLO2 组件，我们建议展示它对几个大脑神经元电特性的贡献 显着表达的区域。这样可以更全面地了解电流 确定神经元电活动并可能揭示 SLO2 通道作为有用的药理学靶点 用于控制癫痫和其他癫痫疾病。因为 SLO2 通道显着表达 在纹状体中，它们也可能是治疗帕金森病和治疗的有用目标 的抑郁症。除了显示 SLO2 通道对神经元电的贡献 兴奋性方面，我们还将揭示更多有关 SLO2 K+ 电流激活机制的信息。我们之前 发现 SLO2 K+ 电流由 Na+ 通过持续向内的钠进入而激活 电导。因此，我们将确定携带此类钠通道的一个或多个钠通道的遗传身份。 能够激活 SLO2 通道的持续钠电流。我们还将调查功能 携带持续 Na+ 电流的钠通道与 SLO2 Na+ 激活之间的关系 渠道。这些实验将在异源系统中进行，我们将在其中重建一个 SLO2-钠通道耦合系统，并在实验中使用来自天然的单膜贴片 可以在神经元中研究钠通道和 SLO2 通道的功能相互作用 钠进入仅限于贴片的限制条件。