BLOCK OF N-METHYL-D-ASPARTATE-ACTIVATED CURRENT BY THE ANTICONVULSANT MK-801 - SELECTIVE BINDING TO OPEN CHANNELS
BLOCK OF N-METHYL-D-ASPARTATE-ACTIVATED CURRENT BY THE ANTICONVULSANT MK-801 - SELECTIVE BINDING TO OPEN CHANNELS
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DOI：
10.1073/pnas.85.4.1307
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发表时间：
1988-02-01
影响因子：
11.1
通讯作者：
BEAN, BP
中科院分区：
文献类型：
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作者：
HUETTNER, JE;BEAN, BP
应用全细胞和单通道记录技术，研究了抗惊厥药MK-801 {（+）-5-甲基-10，11-二氢-5H-二苯并[a，d]-环庚烯-5，10-亚胺马来酸盐}对大鼠新皮层神经元兴奋性氨基酸反应的影响。MK-801对N-甲基-D-天冬氨酸（N-Me-D-Asp）诱导的电流产生进行性、持久性阻断。然而，在N-Me-D-Asp反应被抑制期间，对使君子酸或红藻氨酸的反应没有影响，表明N-Me-D-Asp受体和红藻氨酸/使君子酸受体打开了不同的离子通道群体。MK-801的结合和解结合似乎仅在N-Me-D-Asp操作的通道处于递质激活状态时才可能：MK-801仅在与N-Me-D-Asp同时施用时有效，并且通过连续暴露于N-Me-D-Asp [时间常数（τ）. apprxeq.在-70至-80 mV下90 min]。在连续施加N-Me-D-Asp期间从阻断的恢复是强烈的电压依赖性的，在正电位（τ）下更快。. apprxeq.在+30 mV下2 min）。Mg 2+被认为阻断N-Me-D-Asp激活的离子通道，在负膜电位下可抑制MK-801的阻断作用。在单通道记录从外向补丁，MK-801大大降低了通道活动引起的应用N-Me-D-Asp，但没有显着改变占主导地位的单一电导。与开放通道阻滞机制一致，MK-801以剂量依赖性方式减少平均通道开放时间。
Whole-cell and single-channel recording techniques were used to study the action of the anticonvulsant drug MK-801 {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate} on responses to excitatory amino acids in rat neocortical neurons in cell culture. MK-801 caused a progressive, long-lasting blockade of current induced by N-methyl-D-aspartate (N-Me-D-Asp). However, during the time that N-Me-D-Asp responses were inhibited, there was no effect on responses to quisqualate or kainate, suggesting that N-Me-D-Asp receptors and kainate/quisqualate receptors open separate populations of ion channels. Binding and unbinding of MK-801 seems to be possible only if the N-Me-D-Asp-operated channel is in the transmitter-activated state: MK-801 was effective only when applied simultaneously with N-Me-D-Asp, and recovery from MK-801 blockade was speeded by continuous exposure to N-Me-D-Asp [time constant (.tau.) .apprxeq. 90 min at -70 to -80 mV]. Recovery from block during continuous application of N-Me-D-Asp was strongly voltage dependent, being faster at positive potentials (.tau. .apprxeq. 2 min at + 30 mV). Mg2+, which is thought to block the N-Me-D-Asp-activated ion channel, inhibited blockade by MK-801 at negative membrane potentials. In single-channel recordings from outside-out patches, MK-801 greatly reduced the channel activity elicited by application of N-Me-D-Asp but did not significantly alter the predominant unitary conductance. Consistent with an open-channel blocking mechanism, the mean channel open time was reduced by MK-801 in a dose-dependent manner.