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首页> 外文期刊>Alcohol >Ethanol inhibition of recombinant NR1/2A receptors: effects of heavy metal chelators and a zinc-insensitive NR2A mutant.
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Ethanol inhibition of recombinant NR1/2A receptors: effects of heavy metal chelators and a zinc-insensitive NR2A mutant.

机译：乙醇对重组NR1 / 2A受体的抑制作用：重金属螯合剂和对锌不敏感的NR2A突变体的作用。

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N-methyl-D-aspartate (NMDA) receptors are a subtype of ionotropic glutamate receptors that are highly expressed in brain neurons. These receptors are calcium permeable and regulate various forms of plasticity, including long-term potentiation of glutamate synapses. Acutely, ethanol inhibits the function of NMDA receptors, and chronic exposure of neurons to ethanol is associated with enhanced NMDA receptor function during withdrawal. Results from previous studies with recombinant NMDA receptors have demonstrated that subunit composition influences the ethanol sensitivity of NMDA receptors, with NR2A-containing receptors often showing greater inhibition by ethanol than shown by those containing other NR2 subunits. NR2A-containing NMDA receptors are particularly sensitive to other modulators of channel function, including heavy metals such as zinc. Although zinc inhibits NMDA receptors at micromolar concentrations through a voltage-dependent interaction with a channel site, NR2A-containing receptors are inhibited by low nanomolar concentrations of zinc in a voltage-independent manner. In this study, we examined the effects of ethanol on NR1/NR2A receptors expressed in human embryonic kidney 293 (HEK 293) cells recorded under conditions in which the effects of zinc are minimized. Under control conditions, ethanol (100 mM) inhibited peak and steady-state currents of NR1/2A receptors by 35%-40%. Inclusion of the heavy metal chelator ethylenediaminetetraacetic acid [(EDTA); 10 microM] or other chelating compounds in the experimental solution augmented NMDA-stimulated currents, as previously described. In the presence of EDTA (10 microM), the inhibition of NR1/2A currents by 100 mM ethanol was reduced to approximately 28%. As expected, currents recorded from cells expressing the NR1 subunit and a zinc-insensitive NR2A mutant (H128S) were not augmented by zinc chelators. In these cells, ethanol (100 mM) inhibited NMDA receptor currents by approximately 28%, and this inhibition was unaffected by EDTA. These resultssupport the suggestion that low levels of zinc present in experimental solutions may affect the apparent ethanol sensitivity of NMDA receptors containing the NR2A subunit.
机译：N-甲基-D-天冬氨酸（NMDA）受体是离子型谷氨酸受体的一种亚型，在脑神经元中高度表达。这些受体是钙可渗透的并且调节各种形式的可塑性，包括谷氨酸突触的长期增强。急性地，乙醇抑制NMDA受体的功能，并且神经元长期暴露于乙醇与戒断期间增强的NMDA受体功能有关。以前使用重组NMDA受体进行的研究结果表明，亚单位的组成会影响NMDA受体的乙醇敏感性，与含其他NR2亚基的受体相比，含NR2A的受体对乙醇的抑制作用通常更大。含NR2A的NMDA受体对其他通道功能调节剂特别敏感，包括锌等重金属。尽管锌通过与通道位点的电压依赖性相互作用抑制了微摩尔浓度的NMDA受体，但是低纳摩尔浓度的锌以电压依赖性方式抑制了含NR2A的受体。在这项研究中，我们检查了乙醇对在使锌的作用最小化的条件下记录的人类胚胎肾293（HEK 293）细胞中表达的NR1 / NR2A受体的影响。在控制条件下，乙醇（100 mM）将NR1 / 2A受体的峰值和稳态电流抑制了35％-40％。包含重金属螯合剂乙二胺四乙酸[（EDTA）;如前所述，实验溶液中的10 microM]或其他螯合化合物会增加NMDA刺激的电流。在EDTA（10 microM）存在下，100 mM乙醇对NR1 / 2A电流的抑制作用降低至约28％。如预期的那样，锌螯合剂不会增加从表达NR1亚基和对锌不敏感的NR2A突变体（H128S）的细胞记录的电流。在这些细胞中，乙醇（100 mM）抑制NMDA受体电流约28％，并且这种抑制不受EDTA的影响。这些结果支持以下建议：实验溶液中锌含量低可能会影响含有NR2A亚基的NMDA受体的表观乙醇敏感性。

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