Suárez Luz M, Solís José M
Servicio de Neurobiología-Investigación, Hospital Ramón y Cajal, Madrid 28034, Spain.
Eur J Neurosci. 2006 Jul;24(2):405-18. doi: 10.1111/j.1460-9568.2006.04911.x. Epub 2006 Jul 12.
We have previously shown that activation of presynaptic N-methyl-d-aspartate (NMDA) receptors (NMDAR) enhances the amplitude of the presynaptic fibre volley (FV) evoked in Schaffer collateral axons of rat hippocampal slices, by a mechanism independent of extracellular Ca(2+). Here we compared the pharmacological characteristics of presynaptic NMDARs affecting axon excitability (activated by 10-300 microM NMDA for 10 min), with those mediating field excitatory postsynaptic potentials (NMDA-fEPSP). We found that NMDA-induced potentiation was completely inhibited by NVP-AAM077, an antagonist of NR2A-containing NMDAR, but not by ifenprodil, an NR2B-selective antagonist. The inhibitor of the glycine-binding site in NMDARs, 7-clorokynurenic acid (7-CK), was more potent against NMDA-fEPSP (IC(50) = 6.3 +/- 1.3 microM) than against the NMDA-induced FV potentiation (IC(50) = 26.5 +/- 1.3 microM). Moreover, both post- and presynaptic NMDAR-mediated phenomena were enhanced by glycine and d-serine, but taurine, an endogenous analogue of glycine, only enhanced the latter (EC(50) = 19 microM). Taurine was able to block the inhibitory effect of low doses of 7-CK on NMDA-induced FV potentiation, while glycine and d-serine only reduced the effects of higher concentrations of this drug. Surprisingly, the enhancing effect of taurine on NMDA-induced FV potentiation was blocked when it was co-applied with glycine. Furthermore, the glutamate released synaptically with a train of stimuli also increased FV amplitude by a mechanism dependent on NMDARs; this was potentiated by taurine but not by co-application of taurine and glycine. These results reveal that presynaptic NMDARs have unique properties that mediate the facilitation of axon excitability.
我们之前已经表明，突触前N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）的激活通过一种不依赖细胞外Ca(2+)的机制增强了大鼠海马切片中Schaffer侧支轴突诱发的突触前纤维群峰电位（FV）的幅度。在此，我们比较了影响轴突兴奋性的突触前NMDAR（由10 - 300 microM NMDA激活10分钟）与介导场兴奋性突触后电位（NMDA-fEPSP）的突触前NMDAR的药理学特性。我们发现，NMDA诱导的增强作用被含NR2A的NMDAR拮抗剂NVP - AAM077完全抑制，但未被NR2B选择性拮抗剂ifenprodil抑制。NMDAR中甘氨酸结合位点的抑制剂7 - 氯犬尿氨酸（7 - CK）对NMDA - fEPSP（IC(50) = 6.3 +/- 1.3 microM）的作用比对NMDA诱导的FV增强作用（IC(50) = 26.5 +/- 1.3 microM）更强。此外，甘氨酸和D - 丝氨酸增强了突触后和突触前NMDAR介导的现象，但甘氨酸的内源性类似物牛磺酸仅增强了后者（EC(50) = 19 microM）。牛磺酸能够阻断低剂量7 - CK对NMDA诱导的FV增强作用的抑制效应，而甘氨酸和D - 丝氨酸仅降低该药物较高浓度时的效应。令人惊讶的是，当牛磺酸与甘氨酸共同应用时，其对NMDA诱导的FV增强作用的增强效应被阻断。此外，与一串刺激同步释放的谷氨酸也通过一种依赖NMDAR的机制增加FV幅度；这被牛磺酸增强，但未被牛磺酸和甘氨酸共同应用增强。这些结果表明，突触前NMDAR具有介导轴突兴奋性促进作用的独特特性。
