DEXTRORPHAN AS A PROBE FOR RECOMBINANT NMDA RECE

右旋美沙芬是N-甲基-N-甲基-D-天冬氨酸的选择性非竞争性拮抗剂。 D-天冬氨酸(NMDA)是谷氨酸受体的亚家族。像其他人一样 配体激活的离子通道，NMDA受体似乎是 由几个亚基组成的，这些亚基共同组装形成一个功能 频道。计划研究的具体目标是：(1) 鉴定[~3H]右旋吗啡与NMDA受体的亚单位 相互作用和(2)阐明特定的结构域 负责[~3H]右旋美沙芬与NMDA的相互作用 受体操作的离子通道。放射性配基结合研究将是 用于表征膜制剂中的[~3H]右旋沙芬结合 从瞬时转基因的COS细胞中获得 突变型重组NMDA受体构建。此外，免疫学 将使用技术来确认表达和联合组装 COS细胞膜中的各种亚基。尽管这项研究 这个项目的目标是描述结构决定因素的特征 负责重组人[~3H]右旋糖胺的相互作用 NMDA受体，拟议研究的总体目标是 提供对功能的更完整的机械理解 NMDA受体亚基不同组合的意义。在……里面 反过来，这些研究可能会提供对分子的有用见解。 非竞争性NMDA拟精神特性的基础 拮抗剂以及这些化合物的治疗潜力 减少与中风、头部创伤相关的神经元损伤， 低血糖和持续性抽搐。

Dextrorphan is a selective noncompetitive antagonist of the N-methyl- D-aspartate (NMDA) subfamily of glutamate receptors. Like other ligand-activated ion channels, the NMDA receptor appears to be composed of several subunits which co-assemble to form a functional channel. The specific aims of the projected research are to (1) identify the subunit of the NMDA receptor with which [3H]dextrorphan interacts and (2) to elucidate the specific structural domains responsible for the interaction of [3H]dextrorphan with the NMDA receptor-operated ion channel. Radioligand binding studies will be used to characterize [3H]dextrorphan binding in membrane preparations derived from COS cells transiently transfected with wild-type and mutant recombinant NMDA receptor constructs. In addition, immunologic techniques will be used to confirm both expression and co-assembly of the various subunits in COS cell membranes. Although the research goals of this project are to characterize the structural determinants responsible for the interaction of [3H]dextrorphan with recombinant NMDA receptors, an overall objective of the proposed research is to provide a more complete mechanistic understanding of the functional significance of various combinations of NMDA receptor subunits. In turn, these studies may provide useful insights into the molecular basis for the psychotomimetic properties of noncompetitive NMDA antagonists as well as the therapeutic potential of these compounds to reduce neuronal injury associated with stroke, head trauma, hypoglycemia and sustained convulsions.