Losi G, Vicini S, Neale J
Department of Physiology, Georgetown University, Washington, D.C. 20057-1229 USA.
Neuropharmacology. 2004 Mar;46(4):490-6. doi: 10.1016/j.neuropharm.2003.10.007.
The peptide transmitter N-acetylaspartylglutamate (NAAG) selectively activates the group II metabotropic glutamate receptors. Several reports also suggest that this peptide acts as a partial agonist at N-methyl-D-aspartate (NMDA) receptors but its putative antagonist effects have not been directly tested. To do this, we used whole cell recordings from cerebellar granule cells (CGC) in culture that allow the highest possible resolution of NMDA channel activation. When CGC were activated with equimolar concentrations of NMDA and NAAG, the peptide failed to alter the peak current elicited by NMDA. Very high concentrations of NAAG (100-200 microM) did not significantly reduce the current elicited by 10 microM NMDA or 0.1 microM glutamate, while 400 microM NAAG produced only a very small (less than 15%) reduction in these whole cell currents. Similarly, NAAG (400 microM) failed to significantly alter the average decay time constant or the peak amplitude of NMDA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs). We conclude that high concentrations of the peptide do not exert physiologically relevant antagonist actions on synaptic NMDA receptor activation following vesicular release of glutamate. As an agonist, purified NAAG was found to be at least 10,000-fold less potent than glutamate in increasing "background" current via NMDA receptors on CGC. Inasmuch as it is difficult to confirm that NAAG preparations are completely free from contamination with glutamate at the 0.01% level, the peptide itself appears unlikely to have a direct agonist activity at the NMDA receptor subtypes found in CGC. Recent reports indicate that enhancing the activity of endogenous NAAG may be an important therapeutic approach to excitotoxicity and chronic pain perception. These effects are likely mediated by group II mGluRs, not NMDA receptors.
肽类递质N - 乙酰天冬氨酰谷氨酸（NAAG）可选择性激活II型代谢型谷氨酸受体。一些报道还表明，该肽在N - 甲基 - D - 天冬氨酸（NMDA）受体上作为部分激动剂起作用，但其假定的拮抗作用尚未得到直接测试。为此，我们使用了培养的小脑颗粒细胞（CGC）的全细胞记录，这种记录方式能够实现对NMDA通道激活的最高分辨率。当用等摩尔浓度的NMDA和NAAG激活CGC时，该肽未能改变NMDA引发的峰值电流。非常高浓度的NAAG（100 - 200微摩尔）并未显著降低由10微摩尔NMDA或0.1微摩尔谷氨酸引发的电流，而400微摩尔NAAG仅使这些全细胞电流产生非常小的（小于15%）降低。同样，NAAG（400微摩尔）未能显著改变NMDA受体介导的微小兴奋性突触后电流（mEPSCs）的平均衰减时间常数或峰值幅度。我们得出结论，高浓度的该肽在谷氨酸囊泡释放后对突触NMDA受体激活不发挥生理相关的拮抗作用。作为激动剂，发现纯化的NAAG通过CGC上的NMDA受体增加“背景”电流的效力比谷氨酸至少低10000倍。由于难以确认NAAG制剂在0.01%水平上完全没有谷氨酸污染，该肽本身似乎不太可能在CGC中发现的NMDA受体亚型上具有直接激动剂活性。最近的报道表明，增强内源性NAAG的活性可能是治疗兴奋性毒性和慢性疼痛感知的重要治疗方法。这些作用可能是由II型代谢型谷氨酸受体介导的，而非NMDA受体。
