GLUTAMATE (AMPA) RECPTORS

α -氨基-3羟基-5-甲基异恶唑-4-丙酸

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.