MODULATION OF NMDA RECEPTORS BY TYROSINE KINASES

最近的研究表明，酪氨酸激酶在乙醇中毒的突触可塑性和神经机制中起着重要作用，可能通过增强NMDA受体功能。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。微量的Zn/2+存在于实验记录溶液和体内。因此，Zn/2+，像Mg/2+和质子一样，可以张力性地抑制NMDA受体，特别是记录溶液和体内。因此，与Mg/2+和质子一样，Zn/2+可以张力性地抑制NMDA受体，特别是由NR 1/NR 2A亚基组成的那些，因为这些受体被ZN/2+抑制，IC/50为10 nM。我们已经提供了非受体酪氨酸激酶src降低重组NR 1/NR 2A的Zn/2+敏感性的证据，并且提供了非受体酪氨酸激酶src降低重组NR 1/NR 2A和NR 1/NR 2B受体的Zn/2+敏感性的证据。因此，src引起环境Zn/2+对NR 1/NR 2A受体的紧张性抑制的缓解，这导致NR 1/NR 2A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NR 1/NR 2A受体电流的增强。在这个提议中，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，我们将使用磷酸肽图谱来阐明NR 2A中的酪氨酸磷酸化位点，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性毒性的细胞过程产生广泛的影响。

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.