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，研究大脑神经元的电气特性的最新工作代表 了解钾通道如何控制神经元电活动的兴奋性的突破， 并可能对基本和临床神经科学产生重大影响。我们最近表明 在许多神经元类型中，延迟向外钾电导的最大成分之一， 正常的生理学已经没有注意到，是Na+激活的Slo2（Slack）通道的产物。以前的 哺乳动物神经元中钾电导的研究可能已经忽略了这一重要组成部分 向外电流，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还取出了SLO2 currrent，这是其Na+进入块的次要结果。 由于大多数先前对中枢神经系统神经元电性能的研究已经忽略了大SLO2 组件，我们建议表明其对几个大脑神经元的电特性的贡献 它被显着表达的区域。这将使对电流有更透彻的了解 确定神经元电活动并可能揭示SLO2通道作为有用的药理目标 控制癫痫和其他癫痫发作。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氏病和治疗的有用目标 抑郁症。除了显示SLO2通道对神经元电气的贡献外 兴奋性，我们还将更多地揭示有关Slo2 K+电流激活机制的更多信息。我们以前 发现SLO2 K+电流通过Na+进入通过持续的内向钠激活 电导。因此，我们将确定一个或多个携带此类钠通道的遗传认同 能够激活SLO2通道的持续钠电流。我们还将研究功能 含有持续Na+电流的钠通道和Slo2 Na+激活的关系 频道。这些实验将在异源系统中进行 Slo2-钠通道耦合系统，以及在实验中使用来自天然的单个膜贴 可以在下面研究钠通道和SLO2通道的功能相互作用的神经元 钠入口限于斑块的限制条件。