COMPETITIVE ANTAGONISTS AND PARTIAL AGONISTS AT THE GLYCINE MODULATORY SITE OF THE MOUSE N-METHYL-D-ASPARTATE RECEPTOR
COMPETITIVE ANTAGONISTS AND PARTIAL AGONISTS AT THE GLYCINE MODULATORY SITE OF THE MOUSE N-METHYL-D-ASPARTATE RECEPTOR
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DOI：
10.1113/jphysiol.1990.sp018288
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发表时间：
1990-11-01
影响因子：
5.5
通讯作者：
ASCHER, P
中科院分区：
文献类型：
--
作者：
HENDERSON, G;JOHNSON, JW;ASCHER, P
犬尿酸盐 (Kyn)、7-氯犬尿酸盐 (7-Cl-Kyn)、3-氨基-1-羟基-吡咯烷-2-酮 (HA-966) 和 D-环丝氨酸已知可与甘氨酸位点结合，调节脊椎动物中枢神经元的 N-甲基-D-天冬氨酸 (NMDA) 反应。使用膜片钳和快速灌注技术对原代培养物中的小鼠皮质神经元研究这些化合物的作用，以确定它们是否充当甘氨酸的拮抗剂、部分激动剂和/或反向激动剂。快速药物应用方法可以研究稳态和瞬态反应。稳态响应的分析表明Kyn和7-Cl-Kyn的主要作用是甘氨酸竞争性拮抗剂所预期的那些，Kyn的解离常数为15μM，7-Cl-Kyn的解离常数为0.3μM。浓度跳跃表明，在所有甘氨酸浓度下，特别是在不添加甘氨酸的情况下，Kyn 和 7-Cl-Kyn 的阻断以接近甘氨酸从其结合位点解离的速率进行，并且与拮抗剂浓度无关。 D-环丝氨酸和HA-966的主要作用分别是高效和低效部分激动剂的作用。在不添加甘氨酸的情况下，D-环丝氨酸总是产生增强作用，而HA-966要么产生增强作用，要么产生抑制作用。这可以通过假设存在不同水平的污染甘氨酸来解释。对于 D-环丝氨酸和 HA-966，浓度跳跃产生双相弛豫，其中缓慢成分的起始速率再次接近甘氨酸从其结合位点解离的速率。这些结果可以通过假设（1）Kyn和7-Cl-Kyn是甘氨酸的竞争性拮抗剂，（2）HA-966和D-环丝氨酸是部分激动剂，（3）在不添加甘氨酸的情况下，细胞外溶液中存在一些甘氨酸以及（4）在完全不存在甘氨酸的情况下的反应非常小或可以忽略不计来解释。
Kynurenate (Kyn), 7-chlorokynurenate (7-Cl-Kyn), 3-amino-1-hydroxy-pyrrolid-2-one (HA-966) and D-cycloserine are known to bind to the glycine site that modulates the N-methyl-D-aspartate (NMDA) response of vertebrate central neurones. The effects of these compounds were investigated with patch-clamp and fast-perfusion techniques on mouse cortical neurones in primary culture in an effort to establish whether they act as antagonists, partial agonists and/or inverse agonists of glycine. A fast drug application method allowed the study of both steady-state and transient responses. The analysis of steady-state responses indicates that the main effects of Kyn and 7-Cl-Kyn are those expected from competitive antagonists of glycine, with a dissociation constant of 15 .mu.M for Kyn, and of 0.3 .mu.M for 7-Cl-Kyn. Concentration jumps indicate that at all concentrations of glycine, and in particular in the absence of added glycine, the blockade by Kyn and 7-Cl-Kyn develops at a rate which is close to the rate of dissociation of glycine from its binding site and is independent of antagonist concentration. The main effects of D-cycloserine and of HA-966 are those of partial agonists of high and low efficacy, respectively. In the absence of added glycine, D-cycloserine always produced a potentiation, while HA-966 produced either a potentiation or an inhibition. This can be explained by assuming the presence of a variable level of contaminating glycine. With both D-cycloserine and HA-966, concentration jumps produced biphasic relaxations in which the onset rate of the slow component was, here again, close to the rate of dissociation of glycine from its binding site. These results can be interpreted by assuming that (1) Kyn and 7-Cl-Kyn are competitive antagonists of glycine, (2) HA-966 and D-cycloserine are partial agonists, (3) in the absence of added glycine some glycine is present in the extracellular solution and (4) the response in the total absence of glycine is very small or negligbile.