NMDA RECEPTOR SIGNALING PATHWAYS IN BRAIN

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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.