MOLECULAR STUDIES OF POTASSIUM CHANNELS IN THE HIPPOCAMPUS

海马体钾离子通道的分子研究

• 批准号: 6204873
• 负责人: LILY Y JAN
• 金额: $ 17.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-10 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6204873
• 关键词: Xenopus oocyte; alternatives to animals in research; electrophysiology; gene expression; gene targeting; genetically modified animals; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; long term potentiation; molecular cloning; neural plasticity; neurons; northern blottings; polymerase chain reaction; potassium channel; synapses; transfection; voltage gated channel

The long-term objectives are to molecularly characterize potassium channels and to understand their functional roles in the mammalian brain. Specifically, the plan over the next five years is (1) to study the function and regulation of the Kv1.4 voltage-gated [potassium channels prevent in the axons and nerve terminals of many central neurons, (2) to study the possible role of a G protein-activated potassium channel as an effector that mediates the action of a wide range of neurotransmitter including serotonin, acetylcholine and GABA, and (3) to test the possibility that neuronal excitability is regulated by the energy level of the neuron partly via inhibition of a potassium channel by ATP. In addition to contributing to our understanding of the basic mechanisms underlying the function and plasticity of the mammalian brain, these studies may be relevant to current efforts tin the development of drugs that affect potassium channel function, used for treatment of diseases such as diabetes, arrhythmia, multiple sclerosis, or incontinence. Better understanding of the function and molecular diversity of potassium channels in the mammalian brain may also improve the likelihood of developing regimen to minimize neuronal damage due to ischemia or anoxia or treatments for behavioral disorders. One such disorder, episodic ataxia, has been found to arise from mutations of the Kv1.1 voltage-gated potassium channel. The research design is to first clone potassium channel genes that are expressed in the mammalian brain, and then study these potassium channels using two complimentary approaches. First, expression of cloned potassium channels in cell lines or Xenopus oocytes makes it possible to carry out mechanistic studies on the assembly, function and regulation of individual channel types. Second, expression of wildtype or mutated potassium channels in transgenic mice or removal of the endogenous potassium channels in transgenic mice or removal of the endogenous potassium channel gene function via homologous recombination will be carried out to analyze the function of these potassium channels at the level of central neuronal signaling and behavior.

长期目标是对钾通道进行分子表征 并了解它们在哺乳动物大脑中的功能作用。 具体来说，未来五年的计划是（一）研究 Kv1.4电压门控[钾通道]的功能和调节 防止许多中枢神经元的轴突和神经末梢，（2） 研究 G 蛋白激活的钾通道作为 介导多种神经递质作用的效应器 包括血清素、乙酰胆碱和 GABA，以及 (3) 测试 神经元兴奋性可能受能量水平调节 部分通过 ATP 抑制钾通道来影响神经元。 除了有助于我们理解基本机制 在哺乳动物大脑的功能和可塑性的基础上，这些 研究可能与当前药物开发工作相关 影响钾通道功能，用于治疗疾病 例如糖尿病、心律失常、多发性硬化症或失禁。 更好的 了解钾通道的功能和分子多样性 在哺乳动物大脑中也可能提高发育的可能性 尽量减少因缺血或缺氧或治疗引起的神经元损伤的方案 对于行为障碍。 一种这样的疾病，即阵发性共济失调，已被 发现由 Kv1.1 电压门控钾通道的突变引起。 研究设计首先克隆钾通道基因 在哺乳动物大脑中表达，然后研究这些钾通道 使用两种互补的方法。 一、克隆钾的表达 细胞系或非洲爪蟾卵母细胞中的通道使​​得可以进行 个体组装、功能和调节的机制研究 渠道类型。 二、野生型或突变型钾的表达 转基因小鼠中的通道或内源性钾通道的去除 在转基因小鼠中或去除内源性钾通道基因 将通过同源重组进行功能分析 这些钾通道在中枢神经元水平的功能 信号和行为。