Gafurov B, Urazaev A K, Grossfeld R M, Lieberman E M
Department of Physiology, The Brody School of Medicine of East Carolina University, Greenville, NC 27858, USA.
Neuroscience. 2001;106(1):227-35. doi: 10.1016/s0306-4522(01)00271-8.
Glial cell hyperpolarization previously has been reported to be induced by high frequency stimulation or glutamate. We now report that it also is produced by the glutamate-containing dipeptide N-acetylaspartylglutamate (NAAG), by its non-hydrolyzable analog beta-NAAG, and by NAAG in the presence of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a potent inhibitor of the NAAG degradative enzyme glutamate carboxypeptidase II. The results indicate that NAAG mimics the effect of nerve fiber stimulation on the glia. Although glutamate has a similar effect, the other presumed product of NAAG hydrolysis, N-acetylaspartate, is without effect on glial cell membrane potential, as is aspartylglutamate (in the presence of 2-PMPA). The hyperpolarization induced by stimulation, glutamate, NAAG, beta-NAAG, or NAAG plus 2-PMPA is completely blocked by the Group II metabotropic glutamate receptor antagonist (S)-alpha-ethylglutamate but is not altered by antagonists of Group I or III metabotropic glutamate receptors. The N-methyl-D-aspartate receptor antagonist MK801 reduces but does not eliminate the hyperpolarization generated by glutamate, NAAG or stimulation. These results, in combination with those of the preceding paper, are consistent with the premise that NAAG could be the primary axon-to-glia signaling agent. When the unstimulated nerve fiber is treated with cysteate, a glutamate reuptake blocker, there is a small hyperpolarization of the glial cell that can be substantially reduced by pretreatment with 2-PMPA before addition of cysteate. A similar effect of cysteate is seen during a 50 Hz/5 s stimulation. From these results we suggest that glutamate derived from NAAG hydrolysis appears in the periaxonal space under the conditions of these experiments and may contribute to the glial hyperpolarization.
先前有报道称，高频刺激或谷氨酸可诱导神经胶质细胞超极化。我们现在报告，含谷氨酸的二肽N-乙酰天冬氨酰谷氨酸（NAAG）、其不可水解类似物β-NAAG以及在NAAG降解酶谷氨酸羧肽酶II的强效抑制剂2-(膦酰甲基)-戊二酸（2-PMPA）存在下的NAAG，也能产生这种超极化。结果表明，NAAG模拟了神经纤维刺激对神经胶质细胞的作用。尽管谷氨酸有类似作用，但NAAG水解的另一种推测产物N-乙酰天冬氨酸对神经胶质细胞膜电位没有影响，天冬氨酰谷氨酸（在2-PMPA存在下）也是如此。由刺激、谷氨酸、NAAG、β-NAAG或NAAG加2-PMPA诱导的超极化被II组代谢型谷氨酸受体拮抗剂(S)-α-乙基谷氨酸完全阻断，但不受I组或III组代谢型谷氨酸受体拮抗剂的影响。N-甲基-D-天冬氨酸受体拮抗剂MK801可减少但不能消除由谷氨酸、NAAG或刺激产生的超极化。这些结果与前文结果相结合，符合NAAG可能是轴突到神经胶质细胞主要信号传导剂的前提。当用谷氨酸再摄取阻滞剂半胱氨酸处理未受刺激的神经纤维时，神经胶质细胞会出现轻微超极化，在加入半胱氨酸之前先用2-PMPA预处理可使其大幅降低。在50Hz/5s刺激期间也观察到半胱氨酸有类似作用。从这些结果我们推测，在这些实验条件下，NAAG水解产生的谷氨酸出现在轴突周围间隙，可能导致神经胶质细胞超极化。
