Tyrosine dephosphorylation and ethanol inhibition of N-methyl-D-aspartate receptor function
Tyrosine dephosphorylation and ethanol inhibition of N-methyl-D-aspartate receptor function
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DOI：
10.1074/jbc.m210167200
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发表时间：
2003-03-28
影响因子：
4.8
通讯作者：
Browning, MD
中科院分区：
文献类型：
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作者：
Alvestad, RM;Grosshans, DR;Browning, MD
乙醇对N-甲基-D-天冬氨酸受体（NMDAR）的抑制作用在几个脑区有很好的记录。然而，乙醇影响NMDAR的分子机制还不清楚。与乙醇的抑制作用相反，NMDAR的磷酸化增强通道电流（Lu，W.是的，Xiong，Z. G.，雷，S.，奥瑟，B。一、杜德克，E.，布朗宁，M. D、和MacDonald，J.F.等人（1999）Nat.Neurosci. 2，331 - 338）。我们先前已经表明，蛋白激酶C激活剂诱导NMDAR的酪氨酸磷酸化和增强（Grosshans，D. R.，克莱顿，D. R.，Coultrap，S. J.，和布朗宁，M. D.等人（2002）Nat.Neurosci. 5，27 - 33）。因此，我们假设乙醇抑制NMDAR可能是由于NMDAR亚基酪氨酸磷酸化的变化。为了支持这一假设，我们发现，NR2A和NR2B亚基的酪氨酸磷酸化显着减少后，海马切片原位暴露于100 nM乙醇。具体地，NR2B上的酪氨酸1472的磷酸化降低了23.5%。这些数据表明乙醇可能通过激活酪氨酸磷酸酶抑制NMDAR的可能机制。电生理学研究表明，乙醇抑制NMDAR场兴奋性突触后电位斜率和振幅的程度与我们实验室和其他人先前报道的相似（Schummers，J.，Bentz，S.，和布朗宁，M. D. 03 The Dog of the Woman（1997）Res. 21，404 - 408）。列入bpV（phen），一种有效的磷酸酪氨酸磷酸酶抑制剂，在记录室之前和乙醇暴露过程中显着降低了抑制作用的乙醇对NMDAR场兴奋性突触后电位。总之，这些数据表明，磷酸酶介导的NMDAR亚基的去磷酸化可能在介导乙醇对N-甲基-D-天冬氨酸受体的抑制作用中发挥重要作用。
The inhibitory effect of ethanol on N-methyl-D-aspartate receptors (NMDARs) is well documented in several brain regions. However, the molecular mechanisms by which ethanol affects NMDARs are not well understood. In contrast to the inhibitory effect of ethanol, phosphorylation of the NMDAR potentiates channel currents (Lu, W. Y., Xiong, Z. G., Lei, S., Orser, B. A., Dudek, E., Browning, M. D., and MacDonald, J. F. (1999) Nat. Neurosci. 2, 331-338). We have previously shown that protein kinase C activators induce tyrosine phosphorylation and potentiation of the NMDAR (Grosshans, D. R., Clayton, D. R., Coultrap, S. J., and Browning, M. D. (2002) Nat. Neurosci. 5, 27-33). We therefore hypothesized that the ethanol inhibition of NMDARs might be due to changes in tyrosine phosphorylation of NMDAR subunits. In support of this hypothesis, we found that tyrosine phosphorylation of both NR2A and NR2B subunits was significantly reduced following in situ exposure of hippocampal slices to 100 nM ethanol. Specifically, phosphorylation of tyrosine 1472 on NR2B was reduced 23.5%. These data suggest a possible mechanism by which ethanol may inhibit the NMDAR via activation of a tyrosine phosphatase. Electrophysiological studies demonstrated that ethanol inhibited NMDAR field excitatory postsynaptic potential slope and amplitude to a similar degree as previously reported by our laboratory and others (Schummers, J., Bentz, S., and Browning, M. D. (1997) Alcohol Clin. Exp. Res. 21, 404-408). Inclusion of bpV(phen), a potent phosphotyrosine phosphatase inhibitor, in the recording chamber prior to and during ethanol exposure significantly reduced the inhibitory effect of ethanol on NMDAR field excitatory postsynaptic potentials. Taken together, these data suggest that phosphatase-mediated dephosphorylation of NMDAR subunits may play an important role in mediating the inhibitory effects of ethanol on the N-methyl-D-aspartate receptor.