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首页> 外文期刊>Alcohol >Differential effects of TM4 tryptophan mutations on inhibition of N-methyl-D-aspartate receptors by ethanol and toluene
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Differential effects of TM4 tryptophan mutations on inhibition of N-methyl-D-aspartate receptors by ethanol and toluene

机译：TM4色氨酸突变对乙醇和甲苯抑制N-甲基-D-天冬氨酸受体的差异影响

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摘要

The voluntary use and abuse of alcohol and inhalants is a recognized health problem throughout the world. Previous studies have shown that these agents affect brain function in a variety of ways including direct inhibition of key ion channels that regulate neuronal excitability. Among these, the N-methyl-D-aspartate (NMDA) receptor is particularly important given its key role in glutamatergic synaptic transmission, neuronal plasticity and learning and memory. Previous studies from this laboratory and others have identified key residues within transmembrane (TM) domains of the NMDA receptor that appear to regulate its sensitivity to alcohol and anesthetics. In this study, we extend these findings and examine the role of a TM4 residue in modulating sensitivity of recombinant NMDA receptors to ethanol and toluene. HEK293 cells were transfected with GluN1-1a and either wild-type or tryptophan-substituted GluN2(A-D) subunits and whole-cell currents were recorded using patch-clamp electrophysiology in the absence or presence of ethanol or toluene. Both ethanol (100 mM) and toluene (1 or 3 mM) reversibly inhibited glutamate-activated currents from wild-type NMDARs with GIuN2B containing receptors showing heightened sensitivity to either agent. Substitution of tryptophan (W) at positions 825, 826, 823 or 850 in the TM4 domain of GIuN2A, GIuN2B, GluN2C or GIuN2D subunits; respectively, significantly reduced the degree of inhibition by ethanol. In contrast, toluene inhibition of glutamate-activated currents in cells expressing the TM4-W mutants was not different from that of the wild-type controls. These data suggest that despite similarities in their action on NMDARs, ethanol and toluene may act at different sites to reduce ion flux through NMDA receptors. (C) 2016 Elsevier Inc. All rights reserved.
机译：志愿使用和滥用酒精和吸入剂是全世界都有一个公认的健康问题。以前的研究表明，这些药剂以各种方式影响脑功能，包括直接抑制调节神经元兴奋性的关键离子通道。其中，鉴于其在谷氨酸杆菌突触传递，神经元塑性和学习和记忆中的关键作用，N-甲基-D-天冬氨酸（NMDA）受体特别重要。从该实验室和其他实验室的先前研究已经确定了NMDA受体的跨膜（TM）结构域内的关键残留物，其似乎调节其对酒精和麻醉剂的敏感性。在这项研究中，我们延长了这些发现，并检查了TM4残基在调节重组NMDA受体对乙醇和甲苯的敏感性方面的作用。通过GLUN1-1A转染HEK293细胞，并且在不存在或存在的乙醇或甲苯的情况下使用蛋白质电生理学记录野生型或色氨酸取代的GLUN2（A-D）亚基和全细胞电流。乙醇（100mM）和甲苯（1或3mm）可逆地抑制含有Giun2B的野生型NMDARS的谷氨酸活性电流，所述GIUN2B含有对任一剂的增强敏感性的受体。在Giun2a，Giun2b，glun2c或giun2d亚基的Tm4结构域中的位置825,826,823或850处取代色氨酸（w）;分别显着降低了乙醇的抑制程度。相反，甲苯抑制表达TM4-W突变体的细胞中的谷氨酸活性电流与野生型对照的细胞中的抑制不含量。这些数据表明，尽管它们对NMDARS的作用中的相似性，但乙醇和甲苯可以在不同的部位作用，以减少通过NMDA受体的离子通量。 （c）2016年Elsevier Inc.保留所有权利。

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