The long-term goal of my research is to understand the molecular mechanism by which NMDA receptors are regulated to modulate the strength of synaptic transmission, and to use this information for development of therapeutic strategies to treat neurological and psychiatric diseases. Efficient trafficking of NMDA receptors to synaptic sites is critical for normal excitatory neurotransmission. Intracellular domains of NMDA receptors bind to cytosolic proteins and serve as substrates for protein kinases, thereby regulating synaptic expression and function. NMDA receptors are made up of distinct subunits with unique expression throughout the CNS and with specific function and properties. This proposal addresses the role of the NMDA receptor subunit NR2C in NMDA receptor regulation and trafficking. NR2C confers unique properties on NMDA receptors producing channels relatively insensitive to the voltage-dependent block by magnesium ions. NR2C is highly enriched in cerebellum, thalamus and olfactory bulb. Thus the mechanisms regulating NR2C surface expression and function are likely to be critical in defining NMDA receptor properties in these brain regions. I will use a combination of molcular biology, biochemistry and cell biology to characterize the regulation of NR2C surface expression and the function of NR2C-containing NMDA receptors. The goals are to: 1) Define the role of NR2C-containing NMDA receptors in neuronal survival and elucidate its signaling pathway. 2) Define the role of NR2C phosphorylation in the regulation and trafficking of NMDA receptors. 3) Define the molecular mechanisms underlying subunit-specific regulation of NMDA receptors in cerebellum. The successful completion of these studies is expected to provide the first detailed examination of the regulation of NR2C and provide insight into the funcitonal significance of NR2C-containing receptors for cerebellar funciton.
NMDA receptors are essential for synaptic transmission, synaptic plasticity as well as neuronal development and are implicated in many neurological disorders, including Alzheimer's disease, Parkison's disease and schizophrenia. NMDA receptors also play a major role in mediating the excitotoxicity produced during cerebral ischaemia.