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首页> 外文期刊>Alcohol >Dephosphorylation of GluN2B C-terminal tyrosine residues does not contribute to acute ethanol inhibition of recombinant NMDA receptors.
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Dephosphorylation of GluN2B C-terminal tyrosine residues does not contribute to acute ethanol inhibition of recombinant NMDA receptors.

机译：GluN2B C端酪氨酸残基的去磷酸化不会对重组NMDA受体产生急性乙醇抑制作用。

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摘要

N-methyl-d-aspartate (NMDA) receptors are ion channels activated by the neurotransmitter glutamate and are highly expressed by neurons. These receptors are critical for excitatory synaptic signaling and inhibition of NMDA receptors leads to impaired cognition and learning. Ethanol inhibits NMDA currents at concentrations associated with intoxication and this action may underlie some of the behavioral effects of ethanol. Although numerous sites and mechanisms of action have been tested, the manner in which ethanol inhibits NMDA receptors remains unclear. Recent findings in the literature suggest that ethanol, via facilitation of tyrosine phosphatase activity, may dephosphorylate key tyrosine residues in the C-terminus of GluN2B subunits resulting in diminished channel function. To directly test this hypothesis, we engineered GluN2B mutants that contained phenylalanine in place of tyrosine at three different sites and transiently expressed them with the GluN1 subunit in human embryonic kidney (HEK) cells. Whole-cell patch clamp electrophysiology was used to record glutamate-activated currents in the absence and presence of ethanol (10-600?mM). All mutants were functional and did not differ from one another with respect to current amplitude, steady-state to peak ratio, or magnesium block. Analysis of ethanol dose-response curves showed no significant difference in IC50 values between wild-type receptors and Y1252F, Y1336F, Y1472F or triple Y-F mutants. These findings suggest that dephosphorylation of C-terminal tyrosine residues does not account for ethanol inhibition of GluN2B receptors.
机译：N-甲基-d-天冬氨酸（NMDA）受体是由神经递质谷氨酸激活的离子通道，并由神经元高度表达。这些受体对于兴奋性突触信号传导至关重要，并且抑制NMDA受体会导致认知和学习受损。乙醇会在与中毒有关的浓度下抑制NMDA电流，这种作用可能是乙醇的某些行为效应的基础。尽管已经测试了许多位点和作用机理，但是乙醇抑制NMDA受体的方式仍不清楚。文献中的最新发现表明，乙醇可通过促进酪氨酸磷酸酶活性来使GluN2B亚基C末端的关键酪氨酸残基去磷酸化，从而导致通道功能减弱。为了直接检验该假设，我们设计了在三个不同位点包含苯丙氨酸代替酪氨酸的GluN2B突变体，并在人类胚胎肾脏（HEK）细胞中瞬时表达了GluN1亚基。全细胞膜片钳电生理学用于记录在不存在和存在乙醇（10-600？mM）的情况下谷氨酸激活的电流。所有突变体都具有功能，并且在电流幅度，稳态峰比或镁阻滞方面彼此没有区别。乙醇剂量反应曲线的分析表明，野生型受体与Y1252F，Y1336F，Y1472F或三重Y-F突变体之间的IC50值无显着差异。这些发现表明，C末端酪氨酸残基的去磷酸化不能解释乙醇对GluN2B受体的抑制作用。

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