Buller A L, Larson H C, Morrisett R A, Monaghan D T
Department of Pharmacology, University of Nebraska Medical Center, Omaha 68198-6260, USA.
Mol Pharmacol. 1995 Oct;48(4):717-23.
Ethanol inhibits N-methyl-D-aspartate (NMDA) receptor-mediated responses at pharmacologically relevant concentrations, suggesting that inhibition of NMDA receptors may underlie some of the actions of ethanol in the central nervous system. We examined the ability of glycine to modulate ethanol inhibition of four recombinant heteromeric NMDA receptors (NR1a/NR2A through NR2D) expressed in Xenopus oocytes. Ethanol dose-response analysis revealed enhanced inhibitory efficacy of ethanol in the presence of subsaturating glycine concentrations at the NR1/NR2A, NR1/NR2C, and NR1/NR2D receptors. When assayed over a range of glycine concentrations, ethanol exhibited both glycine-reversible and glycine-independent inhibition of NMDA receptors. In contrast, ethanol inhibition of recombinant NMDA receptors was independent of NMDA concentration. Glycine reversal of ethanol inhibition suggested that ethanol might lower the affinity of glycine for the NMDA receptor and thereby decrease response magnitude. Consistent with this hypothesis, ethanol significantly reduced glycine affinity at NR1/NR2A and NR1/NR2C receptors. Evaluation of the glycine-independent component of ethanol inhibition demonstrated that in the presence of saturating concentrations of glycine, the NR1/NR2A and NR1/NR2B receptors were more sensitive to ethanol than the NR1/NR2C and NR1/NR2D receptors. Activation of the NR1/NR2D heteromers by NMDA and low concentrations of glycine elicited responses characterized by an initial peak followed by a lower-amplitude plateau response, which is consistent with glycine-sensitive desensitization as previously described for native NMDA receptors. In addition, nondesensitizing NR1/NR2B responses elicited in the presence of subsaturating concentrations of glycine were frequently converted into desensitizing responses by the addition of ethanol, an effect that was reversed with increasing glycine concentrations. The ability of ethanol to promote glycine-sensitive desensitization further suggests an interaction between glycine and ethanol inhibition of the NMDA receptor. Taken together, the results of the present report demonstrate that ethanol inhibition of NMDA receptors has both glycine-reversible and glycine-independent components, suggesting two distinct molecular mechanisms for ethanol inhibition of NMDA receptors.
乙醇在药理学相关浓度下会抑制N-甲基-D-天冬氨酸（NMDA）受体介导的反应，这表明NMDA受体的抑制作用可能是乙醇在中枢神经系统中某些作用的基础。我们研究了甘氨酸调节乙醇对非洲爪蟾卵母细胞中表达的四种重组异聚体NMDA受体（从NR1a/NR2A到NR2D）抑制作用的能力。乙醇剂量反应分析显示，在NR1/NR2A、NR1/NR2C和NR1/NR2D受体处，当甘氨酸浓度未饱和时，乙醇的抑制效力增强。当在一系列甘氨酸浓度下进行测定时，乙醇对NMDA受体表现出甘氨酸可逆性抑制和甘氨酸非依赖性抑制。相比之下，乙醇对重组NMDA受体的抑制作用与NMDA浓度无关。乙醇抑制作用的甘氨酸逆转表明，乙醇可能会降低甘氨酸对NMDA受体的亲和力，从而降低反应幅度。与该假设一致，乙醇显著降低了NR1/NR2A和NR1/NR2C受体处的甘氨酸亲和力。对乙醇抑制作用的甘氨酸非依赖性成分的评估表明，在甘氨酸饱和浓度存在的情况下，NR1/NR2A和NR1/NR2B受体比NR1/NR2C和NR1/NR2D受体对乙醇更敏感。NMDA和低浓度甘氨酸对NR1/NR2D异聚体的激活引发的反应特征为初始峰值，随后是较低幅度的平台期反应，这与先前描述的天然NMDA受体的甘氨酸敏感脱敏一致。此外，在未饱和甘氨酸浓度存在的情况下引发的非脱敏性NR1/NR2B反应，通过添加乙醇经常会转变为脱敏性反应，随着甘氨酸浓度的增加，这种效应会逆转。乙醇促进甘氨酸敏感脱敏的能力进一步表明甘氨酸与乙醇对NMDA受体的抑制之间存在相互作用。综上所述，本报告的结果表明，乙醇对NMDA受体的抑制作用具有甘氨酸可逆性和甘氨酸非依赖性成分，这表明乙醇抑制NMDA受体存在两种不同的分子机制。
