GLUTAMATE (AMPA) RECPTORS

α-氨基-3-羟基-5-甲基异恶唑-4-丙酸 谷氨酸受体亚型被认为是突触 哺乳动物大脑的可塑性。它与癫痫有关， 兴奋性毒性 因此，调节AMPA的机制和因素 受体活性具有相当大的意义。的重点 项目是确定AMPA受体的功能特性 和相关的离子通道的化合物 受体功能长期目标是揭示 AMPA受体在突触可塑性和长时程增强中的作用 （LTP）。LTP是突触可塑性的一种形式， 学习和记忆。应注意，在纯化过程中， 与溶解的AMPA高亲和力结合的工艺肝素 受体和改变的通道动力学。肝素和 其他糖胺聚糖（GAG）对单通道动力学的影响 将测定纯化和重构的AMPA受体。 生化研究表明，肝素对 膜相关AMPA受体。复溶期间 实验肝素和硫酸葡聚糖诱导AMPA通道 非常高的导电性。 因此，本项目将定义 负责膜相关的反应的差异 和糖胺聚糖的溶解受体。 这将是 通过重组粗品的电生理学分析实现 用特定酶处理过的突触制备物 来去除某些糖胺聚糖该项目还将 研究糖胺聚糖在增加 AMPA受体通道之间的协同性以及 对AMPA有中枢活性的药物（苯甲酰吡啶衍生物） 受体和相关通道。这些药物已被证明 导致大鼠保持分数的显著改善， 人类受试者测试各种记忆任务，可能是由于 AMPA受体和相关离子通道的调节。

Alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptor is believed w be central to synaptic plasticity in the mammalian brain. It is implicated in epilepsy and excitotoxicity. 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 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 indicate that heparin has little effect on membrane associated AMPA receptors. During reconstitution 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 crude synaptic preparations that have been treated with specific enzymes to remove certain glycosaminoglycans. This project will also investigate the role of glycosaminoglycans on the increased 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 AMPA receptors and associated ion channeLS.