Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-D-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism.
Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-D-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism.
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有证据表明，N-甲基-D-天冬氨酸受体上电压依赖性 Mg2 阻断的丧失是神经元代谢抑制过程中受体激活的基础。
DOI：
10.1111/j.1471-4159.1992.tb08430.x
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发表时间：
1992
影响因子：
4.7
通讯作者：
Nicklas,WJ
中科院分区：
文献类型：
--
作者：
Zeevalk,GD;Nicklas,WJ
在本研究中，在第 13 天的胚胎鸡视网膜中检查了代谢应激期间 Mg2+ 阻断 N-甲基-D-天冬氨酸 (NMDA) 受体的重要性。视网膜暴露于温和的代谢应激条件下（即，用 1 mMiodoacetate 阻断糖酵解 30 分钟）会出现急性组织学胞浆和神经炎肿胀，并且 γ-氨基丁酸 (GABA) 释放到介质中增加。这些代谢应激的急性症状被糖酵解药理学阻断期间存在的 NMDA 拮抗剂消除，在细胞外谷氨酸或天冬氨酸不存在净增加的情况下发生，并且不受培养介质中存在或不存在 Ca2+ 的影响。在细胞外配体不增加的情况下 NMDA 受体激活的一种可能的解释是，代谢应激期间的 NMDA 敏感性可能在受体水平上受到控制。代谢应激期间膜电位的去极化可能导致 NMDA 受体通道的 Mg2+ 阻断作用丧失，从而导致谷氨酸的效力增加。为了测试这一点，我们检查了细胞外 Mg2+ 存在或不存在时 NMDA、谷氨酸和红藻氨酸的剂量反应特征以及 Mg2+ 对代谢抑制的影响。在没有 Mg2+ 的情况下，NMDA 或谷氨酸介导的急性毒性的效力增强了两到五倍。省略Mg2+大大降低了产生急性兴奋性毒性所需的最低激动剂浓度；在 1.2 或零 Mg2+ 中，NMDA 分别为 25 μM 与 5 μM，谷氨酸盐为 300 μM 与 10 μM。将外部 Mg2+ 升高至 20 mM 可以完全防止 NMDA 介导的急性毒性作用。相反，不同的外部 Mg2+ 对红藻氨酸诱导的毒性没有影响。在缺乏 Mg2+ 的情况下，由代谢抑制引起的急性毒性不会增强，但会因细胞外 Mg2+ 的升高而减弱。 Mg2+在代谢抑制期间的保护作用并不与NMDA拮抗剂相加，表明Mg2+的作用是在NMDA受体水平。这些发现与 Mg2+ 阻断在代谢抑制期间解除并且可能是导致 NMDA 受体激活的主要事件的假设一致。
In this study, the importance of the Mg2+blockade of theN‐methyl‐D‐aspartate (NMDA) receptor during metabolic stress was examined in embryonic day 13 chick retina. Retina exposed to mild conditions of metabolic stress (i.e., blockade of glycolysis with 1 mMiodoacetate for 30 min) underwent acute histological somal and neuritic swelling and an increase in γ‐aminobutyric acid (GABA) release into the medium. These acute signs of metabolic stress were eliminated by NMDA antagonists present during pharmacological blockade of glycolysis, occurred in the absence of a net increase in extracellular glutamate or aspartate, and were not affected by the presence or absence of Ca2+in the incubation medium. One possible explanation for the activation of NMDA receptors in the absence of an increase in extracellular ligand is that NMDA sensitivity during metabolic stress may be governed at the receptor level. Depolarization of membrane potential during metabolic stress may result in the loss of the Mg2+blockade from the NMDA receptor channel, resulting in an increased potency for glutamate. To test this, the dose‐response characteristics for NMDA, glutamate, and kainate in the presence or absence of extracellular Mg2+and the effects of Mg2+on metabolic inhibition were examined. The potency for NMDA‐ or glutamate‐mediated acute toxicity was enhanced two‐ to fivefold in the absence of Mg2+. Omission of Mg2+greatly decreased the minimal concentration of agonist needed to produce acute excitotoxicity; 25 versus 5 μMfor NMDA and 300 versus 10 μMfor glutamate in 1.2 or zero Mg2+, respectively. Elevating external Mg2+to 20 mMcompletely protected against NMDA‐mediated acute toxic effects. In contrast, varying external Mg2+had no effect on kainate‐induced toxicity. Acute toxicity caused by inhibition of metabolism was not potentiated in the absence of Mg2+but was attenuated by elevating extracellular Mg2+. The protective effect of Mg2+during metabolic inhibition was not additive with NMDA antagonists, suggesting that the action of Mg2+was at the level of the NMDA receptor. These findings are consistent with the hypothesis that the Mg2+block is lifted during metabolic inhibition and may be the primary event resulting in NMDA receptor activation.