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.

我们认为，我们最近研究大脑神经元的电特性的工作代表了一种 在理解钾通道如何控制神经元电活动的兴奋性方面取得突破， 并可能对基础神经科学和临床神经科学产生重大影响。我们最近已经证明， 在许多神经元类型中，延迟外向钾电导的最大成分之一，在 正常的生理没有被注意到，它是钠激活的SLO2(松弛)通道的产物。上一首 对哺乳动物神经元钾电导的研究可能忽略了这一大部分 外向电流，因为钠离子通道阻滞剂TTX通常用于哺乳动物K+的研究 通道和TTX还去除了SLO2电流，这是其阻断Na+进入的次要后果。 由于之前对中枢神经系统神经元电学特性的大多数研究都忽略了大的SLO2 组件，我们建议展示它对几个大脑中神经元的电特性的贡献 它被显著表达的地区。这将使我们能够更彻底地了解洋流。 决定神经元的电活动，并可能揭示SLO2通道是有用的药理靶点 用于控制癫痫和其他癫痫发作障碍。因为SLO2通道的显著表达 在纹状体中，它们也可能是治疗帕金森氏病和治疗的有用靶点。 患上了抑郁症。除了显示SLO2通道对神经元电的贡献 兴奋性，我们还将揭示更多关于SLO2 K+电流激活的机制。我们之前 发现钠离子通过持续的内向钠离子进入激活SLO2的K+电流 电导。因此，我们将确定携带这种物质的一个或多个钠离子通道的遗传特性。 一种能够激活SLO2通道的持续钠电流。我们还将调查功能 携带持续性钠电流的钠通道与SLO_2钠离子激活的关系 频道。这些实验将在一个异源系统中进行，在那里我们将重建一个 SLO2-钠通道偶联系统，并在实验中使用天然单膜贴片 可研究钠通道和SLO2通道功能相互作用的神经元 限制钠进入贴片的条件。