MODULATION OF NMDA RECEPTORS BY TYROSINE KINASES

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DESCRIPTION Recent studies suggest that tyrosine kinase plays an important role in synaptic plasticity and neural mechanism of ethanol intoxication, possibly by enhancing NMDA receptor function. However, the mechanisms by which tyrosine kinase potentials NMDA receptor function are unknown. NMDA receptors are allosterically modulated by a variety of endogenous extracellular ions, such as Mg/2+, protons and Zn/2+. Trace amounts of Zn/2+ are present in experimental recording solutions and in vivo. Thus, Zn/2+, like Mg/2+ and protons, could tonically inhibit NMDA receptors, particularly recording solutions and in vivo. Thus, Zn/2+ like Mg/2+ and protons, could tonically inhibit NMDA receptors, particularly those comprised of NR1/NR2A subunits since these receptors are inhibited by ZN/2+ with an IC/50 of 10 nM. We have provided evidence that the non- receptor tyrosine kinase src reduces Zn/2+ sensitivity of recombinant NR1/NR2A and provided evidence that the non-receptor tyrosine kinase src reduces Zn/2+ sensitivity of recombinant NR1/NR2A and NR1/NR2B receptors. Thus, src causes a relief of tonic inhibition of NR1/NR2A receptors by ambient Zn/2+, which results in potentiation of NR1/NR2A receptor currents. In this proposal, we will determine whether our finding can be extended to in potentiation of NR1/NR2A receptor currents in this proposal, we will determine whether our finding can be extended to a potential of NR1/NR2A receptor currents. In this proposal, we will determine whether our finding can be extended to native NMDA receptors in neurons. In addition, we will use phosphopeptide mapping to elucidate the tyrosine phosphorylation sites in NR2A that are critical for modulation of NMDA receptors by src. The proposed study will have broad implications in our understanding of the cellular processes of synaptic plasticity and excitotoxicity.