Department of Biology, Georgetown University, Washington, District of Columbia 20057, USA.
J Neurochem. 2011 Aug;118(4):490-8. doi: 10.1111/j.1471-4159.2011.07338.x. Epub 2011 Jul 1.
A substantial body of data was reported between 1984 and 2000 demonstrating that the neuropeptide N-acetylaspartylglutamate (NAAG) not only functions as a neurotransmitter but also is the third most prevalent transmitter in the mammalian nervous system behind glutamate and GABA. By 2005, this conclusion was validated further through a series of studies in vivo and in vitro. The primary enzyme responsible for the inactivation of NAAG following its synaptic release had been cloned, characterized and knocked out. Potent inhibitors of this enzyme were developed and their efficacy has been extensively studied in a series of animal models of clinical conditions, including stroke, peripheral neuropathy, traumatic brain injury, inflammatory and neuropathic pain, cocaine addiction, and schizophrenia. Considerable progress also has been made in defining further the mechanism of action of these peptidase inhibitors in elevating synaptic levels of NAAG with the consequent inhibition of transmitter release via the activation of pre-synaptic metabotropic glutamate receptor 3 by this peptide. Very recent discoveries include identification of two different nervous system enzymes that mediate the synthesis of NAAG from N-acetylaspartate and glutamate and the finding that one of these enzymes also mediates the synthesis of a second member of the NAAG family of neuropeptides, N-acetylaspartylglutamylglutamate.
1984 年至 2000 年间，大量数据表明，神经肽 N-乙酰基天冬氨酸谷氨酸盐（NAAG）不仅具有神经递质的功能，而且是哺乳动物神经系统中仅次于谷氨酸和 GABA 的第三大常见递质。到 2005 年，通过一系列体内和体外研究进一步验证了这一结论。负责 NAAG 突触释放后失活的主要酶已被克隆、鉴定和敲除。该酶的有效抑制剂已被开发出来，并在一系列临床疾病的动物模型中进行了广泛研究，包括中风、周围神经病、创伤性脑损伤、炎症性和神经性疼痛、可卡因成瘾和精神分裂症。在定义这些肽酶抑制剂的作用机制方面也取得了相当大的进展，这些抑制剂通过激活该肽的突触前代谢型谷氨酸受体 3，增加 NAAG 的突触水平，从而抑制递质释放。最近的发现包括鉴定两种不同的神经系统酶，它们介导 N-乙酰天冬氨酸和谷氨酸合成 NAAG，以及发现其中一种酶还介导另一种 NAAG 神经肽家族成员 N-乙酰基天冬氨酸谷氨酸盐的合成。
