MODULATION AND CHARACTERIZATION OF GLUTAMATE (AMPA) RECEPTORS

谷氨酸 (AMPA) 受体的调节和表征

• 批准号: 6204122
• 负责人: VISHNU D SUPPIRAMANIAM
• 金额: $ 3.04万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6204122
• 关键词: AMPA receptors; SDS polyacrylamide gel electrophoresis; electrochemistry; electrodes; electrophysiology; gap junctions; heparin; immunoprecipitation; laboratory rat; long term potentiation; membrane channels; mucopolysaccharides; neural plasticity; pharmacokinetics; protein reconstitution; psychotropic drugs; pyridine; receptor binding; receptor expression; synapses; voltage /patch clamp

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptor is believed to be central to synaptic plasticity in the mammalian brain. It is implicated in epilepsy and excitoxicity. Thus the mechanisms and factors which modulate AMPA receptor activity are of considerable interest. The focus of this project is to determine the functional properties of AMPA receptors and associated ion channels by the use of compounds which modulate receptor function. The long-term objective is to uncover the role of AMPA receptors in synaptic plasticity and long term potentiation (LTP). LTP is a form of synaptic plasticity thought to underlie learning and memory. It is noted that during the purification process heparin bound with high affinity to solubilized AMPA receptors and altered their channel kinetics. The effects of heparin and other glycosaminoglycans (GAGs) on single channel kinetics of purified and reconstituted AMPA receptors will be determined. Biochemical studies indicated that heparin has little effect on membrane associated AMPA receptors. During reconstruction experiments heparin and dextran sulfate induced AMPA channels of very high conductivity. Thus this project will define the mechanism responsible for the differences in responses of membrane associated and solubilized receptors to glycosaminoglycans. This will be achieved by electrophysiological analysis of reconstituted. This will be achieved by electrophysiological analysis of reconstituted crude synaptic preparations that have been treated with specific enzymes to remove glycosaminoglycans. This project will also investigate the role of glycosaminoglycans on the increase cooperativity among AMPA receptor channels and the effects of centrally active drugs (benzoyl pyridine derivatives) on AMPA receptors and associated channels. These drugs have been shown to result in substantial improvement in retention scores of rats and human subjects tested on various memory tasks, possibly due to modulation of AMP receptors and associated ion channels.

α-氨基-3-羟基-5-甲基异恶唑-4-丙酸 (AMPA) 亚型 谷氨酸受体被认为是突触可塑性的核心 哺乳动物的大脑。它与癫痫和兴奋性毒性有关。因此 调节 AMPA 受体活性的机制和因素是 相当大的兴趣。该项目的重点是确定 AMPA 受体和相关离子通道的功能特性 使用调节受体功能的化合物。长期目标 是为了揭示 AMPA 受体在突触可塑性和长突触中的作用 术语增强（LTP）。 LTP 是突触可塑性的一种形式，被认为 是学习和记忆的基础。值得注意的是，在纯化过程中 处理与溶解的 AMPA 受体高亲和力结合的肝素， 改变了他们的渠道动力学。肝素及其他药物的作用 糖胺聚糖（GAG）对纯化和纯化的单通道动力学的影响 将确定重构的 AMPA 受体。生化研究 表明肝素对膜相关的 AMPA 影响很小 受体。在重建实验中肝素和硫酸葡聚糖 诱导的 AMPA 通道具有非常高的电导率。因此该项目将 定义导致响应差异的机制 膜相关和溶解的糖胺聚糖受体。这 将通过重构的电生理分析来实现。这 将通过重构原油的电生理分析来实现 经过特定酶处理的突触制剂 去除糖胺聚糖。该项目还将调查 糖胺聚糖增加 AMPA 受体之间的协同性 通道和中枢活性药物（苯甲酰吡啶）的作用 衍生物）对 AMPA 受体和相关通道的影响。这些药物有 已被证明可以显着提高保留分数 对大鼠和人类受试者进行各种记忆任务测试，可能是由于 AMP 受体和相关离子通道的调节。