NMDA RECEPTOR SIGNALING PATHWAYS IN BRAIN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 NMDA受体在CNS的许多功能中起关键作用，如突触可塑性和神经病理学条件下细胞死亡的启动。 几年前，我们的实验室首次确定了NMDA受体的4种药理学上不同的亚型。 最近，使用我们开发的亚型选择性拮抗剂，我们首次表明长时程增强和长时程抑制的基本过程是由NMDA受体的不同亚型介导的（J. Neursci. 20：RC 81，1-6，（2000）），并且两种药理学上不同的NMDA受体介导的突触组分可以被鉴定为相同的突触途径（J.Physiol.558.2：451-463（2004））。 我们现在已经开始鉴定与单个NMDA受体亚基特异性相关的信号转导系统。 作为这个项目的一部分，我们已经产生了5个结构编码的细胞内部分的一个NMDA受体亚基，其中每一个包含几个蛋白质-蛋白质相互作用域。 使用下拉的脑裂解物，然后用银染色，我们发现，几个离散的蛋白质被我们的每一个结构。 与UCSF质谱合作，我们现在已经确定了几个信号分子，可以解释NMDA受体激活的许多行动，如突触可塑性，也兴奋性细胞死亡。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NMDA receptors play a key role in many functions of the CNS such as synaptic plasticity and the initiation of cell death in neuropathological conditions. Years ago, our laboratory first identified 4 pharmacologically-distinct subtypes of NMDA receptors. More recently, using subtype-selective antagonists that we developed, we were the first to show that the fundamental processes of long-term potentiation and long-term depression were mediated by different subtypes of NMDA receptors (J. Neursci. 20:RC81, 1-6, (2000)) and that two pharmacologically-distinct NMDA receptor-mediated synaptic components can be identified the same synaptic pathway (J. Physiol. 558.2: 451-463 (2004)). We have now begun identifying signal transduction systems that are specifically associated with individual NMDA receptor subunits. As part of this project, we have generated 5 constructs coding for intracellular portions of one of the NMDA receptor subunits each of which contain several protein-protein interaction domains. Using a pull-down of brain lysate followed by a silver stain, we find that several discrete proteins are recognized by each of our constructs. With the UCSF mass spectrometry collaboration we have now identified several signaling molecules that can account for many of the actions of NMDA receptor activation such as synaptic plasticity and also to excitotoxic cell death.