MODULATION OF NMDA RECEPTORS BY TYROSINE KINASES

近年来的研究表明，酪氨酸激酶可能通过增强NMDA受体的功能，在乙醇中毒的突触可塑性和神经机制中发挥重要作用。然而，酪氨酸激酶电位NMDA受体功能的机制尚不清楚。NMDA受体受多种内源性细胞外离子（如Mg/2+、质子和Zn/2+）的变构调节。微量Zn/2+存在于实验记录溶液和体内。因此，Zn/2+与Mg/2+和质子一样，可以强直抑制NMDA受体，特别是在记录溶液和体内。因此，与Mg/2+和质子一样，Zn/2+可以抑制性地抑制NMDA受体，特别是NR1/NR2A亚基，因为这些受体被Zn/2+抑制的IC/50为10 nM。我们提供的证据表明，非受体酪氨酸激酶src降低了重组NR1/NR2A的Zn/2+敏感性，并提供了非受体酪氨酸激酶src降低重组NR1/NR2A和NR1/NR2B受体Zn/2+敏感性的证据。因此，src导致环境Zn/2+对NR1/NR2A受体的强直性抑制得到缓解，从而导致NR1/NR2A受体电流增强。在本提案中，我们将确定我们的发现是否可以扩展到NR1/NR2A受体电流的增强。在本提案中，我们将确定我们的发现是否可以扩展到NR1/NR2A受体电流的电位。在本提案中，我们将确定我们的发现是否可以扩展到神经元中的天然NMDA受体。此外，我们将使用磷酸肽定位来阐明NR2A中酪氨酸磷酸化位点，这些位点对src调节NMDA受体至关重要。这项研究将对我们理解突触可塑性和兴奋毒性的细胞过程具有广泛的意义。

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.