MODULATION AND CHARACTERIZATION OF GLUTAMATE (AMPA) RECEPTORS

谷氨酸 (AMPA) 受体的调节和表征

• 批准号: 6352971
• 负责人: VISHNU D SUPPIRAMANIAM
• 金额: $ 11万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352971
• 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中心， 哺乳动物的大脑它与癫痫和兴奋毒性有关。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 调节受体功能的化合物的用途。长期目标 是揭示AMPA受体在突触可塑性和长 术语增强（LTP）。LTP是突触可塑性的一种形式， 是学习和记忆的基础应注意，在纯化过程中， 处理与溶解的AMPA受体高亲和力结合的肝素， 改变了它们的通道动力学。肝素和其他药物的作用 糖胺聚糖（GAG）对纯化和 将测定重构的AMPA受体。生化研究 表明肝素对膜结合AMPA影响不大 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 确定造成反应差异的机制， 膜相关的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 将通过重组粗品的电生理学分析来实现 用特定的酶处理过的突触制备物， 除去糖胺聚糖。本项目还将研究 糖胺聚糖对AMPA受体间协同作用的影响 通道和中枢活性药物（苯甲酰吡啶 衍生物）对AMPA受体和相关通道的作用。这些药物具有 已被证明导致保留分数的大幅改善， 大鼠和人类受试者在各种记忆任务中进行测试，可能是由于 AMP受体和相关离子通道的调节。