Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase
Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase
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DOI：
10.1073/pnas.1017856108
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发表时间：
2011-04-19
影响因子：
11.1
通讯作者：
Browning, Michael D.
中科院分区：
文献类型：
--
作者：
Hicklin, Tianna R.;Wu, Peter H.;Browning, Michael D.
酒精对记忆的有害影响是众所周知的。急性酒精诱导的记忆丧失被认为是通过抑制海马中NMDA受体（NMDAR）依赖的长期增强而发生的。我们之前报道过，乙醇对NMDAR功能的抑制和长期增强与NR2B亚基上Tyr（1472）磷酸化的减少有关，并且乙醇对NMDAR场兴奋性突触后电位的抑制被广谱酪氨酸磷酸酶抑制剂减弱。这些数据表明，乙醇的抑制作用可能涉及蛋白酪氨酸磷酸酶。本研究表明，纹状体富集蛋白酪氨酸磷酸酶（STEP）的缺失使NMDAR功能、磷酸化、长期增强以及恐惧调节对乙醇抑制的敏感性降低。此外，当活性STEP蛋白重新导入细胞时，乙醇抑制被“拯救”。综上所述，我们的数据表明，STEP通过NR2B受体上酪氨酸位点的去磷酸化，促进了乙醇对NMDAR功能的抑制，并支持了乙醇的健忘症效应可能需要STEP的假设。
Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr(1472) on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.