The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels.
The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels.
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发表时间：
1990-07
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通讯作者：
A. S. Ramoa;M. Alkondon;Y. Aracava;J. Irons;G. Lunt;S. Deshpande;S. Wonnacott;R. Aronstam;E. Albu
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作者：
A. S. Ramoa;M. Alkondon;Y. Aracava;J. Irons;G. Lunt;S. Deshpande;S. Wonnacott;R. Aronstam;E. Albu
使用电生理学和生化技术研究了 MK-801 [(+]-5-甲基-10,11-二氢-5H-二-苯并[a,d]环庚烯-5,10-亚胺)对外周和中枢烟碱受体的影响。 MK-801降低了峰值幅度并加速了端板电流的衰减。该药物（1-10 µM）除了缩短由 ACh 或 (+)anatoxin-a (AnTX) 激活的通道的平均开放和爆发时间外，还降低了乙酰胆碱 (ACh) 诱导的单通道电流的激活频率。 MK-801 (10-40 microM) 抑制长期去神经支配的大鼠比目鱼肌中的单一电位以及 ACh 和 AnTX 诱导的电位序列。 MK-801 阻断了青蛙缝匠肌和大鼠膈肌因刺激各自的神经而引起的抽搐反应（20-100 µM）。该药物（小于 1 µM）还降低了大鼠视网膜神经节细胞外侧膜片中 AnTX 或 ACh 激活的通道频率，且通道开放时间变化最小。 MK-801 (10-25 microM) 抑制 (-) 尼古丁诱发的大鼠海马突触体释放 γ-氨基[2,3-3H]丁酸；然而，它未能影响[3H](-)尼古丁与脑膜的结合，也未能干扰[125I]α-银环蛇毒素与青蛙肌肉或鱼雷膜的结合。另一方面，MK-801抑制[3H]全氢组氨酸毒素与鱼雷膜的结合，并且这种效果在氨甲酰胆碱存在的情况下更加明显。 AnTX 或任何其他烟碱激动剂均不会增加 [3H]MK-801 与 N-甲基-D-天冬氨酸受体离子通道复合物的结合。 MK-801 的作用在与阻断 N-甲基-D-天冬氨酸受体所需浓度相当的浓度下非常明显。这些结果表明存在至少三种不同类型的烟碱 AChR，所有这些都被 MK-801 非竞争性阻断。
The effects of MK-801 [( +]-5-methyl-10,11-dihydro-5H-di-benzo[a, d]cyclohepten-5,10-imine) on peripheral and central nicotinic receptors were studied using electrophysiological and biochemical techniques. MK-801 depressed the peak amplitude and accelerated the decay of end-plate currents. The drug (1-10 microM) decreased the frequency of activation of acetylcholine (ACh)-induced single-channel currents in addition to shortening the mean open and burst times of channels activated by either ACh or (+)anatoxin-a (AnTX). MK-801 (10-40 microM) depressed the single potentials and trains of ACh and AnTX-induced potentials in chronically denervated rat soleus muscles. MK-801 blocked the twitch responses (20-100 microM) of both frog sartorius and rat diaphragm muscles evoked by stimulation of their respective nerves. Also this drug (less than 1 microM) decreased the frequency of channels activated by AnTX or ACh in outside-out patch membranes of rat retinal ganglion cells with minimal changes in the channel open time. MK-801 (10-25 microM) depressed (-)nicotine-evoked gamma-amino[2,3-3H]butyric acid release from rat hippocampal synaptosomes; however, it failed to affect the binding of [3H](-)nicotine to brain membranes and also failed to interfere with the binding of [125I]alpha-bungarotoxin to either frog muscle or Torpedo membranes. On the other hand, MK-801 inhibited the binding of [3H]perhydrohistrionicotoxin to Torpedo membranes and such an effect was more pronounced in the presence of carbamylcholine. Neither AnTX nor any other nicotinic agonist increased the binding of [3H]MK-801 to the N-methyl-D-aspartate receptor ion channel complex. The actions of MK-801 were evident at concentrations comparable with those needed to block N-methyl-D-aspartate receptors. These results demonstrate the existence of at least three different types of nicotinic AChR, all of which were blocked noncompetitively by MK-801.