Desensitization of NMDA receptor channels is modulated by glutamate agonists
Desensitization of NMDA receptor channels is modulated by glutamate agonists
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DOI：
10.1016/s0006-3495(01)76188-7
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发表时间：
2001-05-01
影响因子：
3.4
通讯作者：
Benveniste, M
中科院分区：
文献类型：
--
作者：
Nahum-Levy, R;Lipinski, D;Benveniste, M
N-甲基-D-天冬氨酸（NMDA）受体有两种不同的脱敏形式。一种形式是当通道被激活时激动剂亲和力减弱，而另一种形式是当通道进入长寿命的非传导状态时脱敏。已经报道了NMDA受体活化后甘氨酸亲和力的减弱。NMDA受体激活的循环反应方案要求对谷氨酸激动剂应观察到伴随的亲和力变化。在这项研究中，峰值和稳态NMDA受体电流的测量产生的谷氨酸的EC 50值相差1.9倍，但没有发现另一种激动剂，L-半胱氨酸-S-硫酸盐（LCSS）的差异。模拟结果表明，在EC 50值的变化可能会掩盖显着程度的脱敏导致进入一个长期的非导电状态的通道。模拟还表明，随着激动剂浓度的增加，脱敏程度的降低是一个很好的指标，存在脱敏导致的激动剂亲和力减弱。谷氨酸盐和LCSS都表现出这种趋势。高亲和力和低亲和力激动剂结合状态之间的亲和力差异为三至八倍，估计从拟合的剂量反应数据与模型包含两种类型的脱敏。这表明NMDA受体的激活引起谷氨酸和甘氨酸亲和力的降低。
Two distinct forms of desensitization have been characterized for N-methyl-D-aspartate (NMDA) receptors. One form results from a weakening of agonist affinity when channels are activated whereas the other form of desensitization results when channels enter a long-lived nonconducting state. A weakening of glycine affinity upon NMDA receptor activation has been reported. Cyclic reaction schemes for NMDA receptor activation require that a concomitant affinity shift should be observed for glutamate agonists. In this study, measurements of peak and steady-state NMDA receptor currents yielded EC50 values for glutamate that differed by 1.9-fold, but no differences were found for another agonist, L-cysteine-S-sulfate (LCSS). Simulations show that shifts in EC50 values may be masked by significant degrees of desensitization resulting from channels entering a long-lived nonconducting state. Simulations also show that a decrease in the degree of desensitization with increasing agonist concentration is a good indicator for the existence of desensitization resulting from a weakening of agonist affinity. Both glutamate and LCSS exhibited this trend. An affinity difference of three- to eightfold between high-and low-affinity agonist-binding states was estimated from fitting of dose-response data with models containing both types of desensitization. This indicates that activation of NMDA receptors causes a reduction in both glutamate and glycine affinities.