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首页> 外文期刊>Neuropharmacology >Effects of N-acetylaspartylglutamate (NAAG) at group II mGluRs and NMDAR.
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Effects of N-acetylaspartylglutamate (NAAG) at group II mGluRs and NMDAR.

机译：第II组mGluRs和NMDAR的N-乙酰天门冬氨酸谷氨酸盐（NAAG）的作用。

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摘要

A group II metabotropic glutamate receptor (mGluR) agonist was recently reported to be clinically efficacious against symptoms of schizophrenia [Patil, S.T., Zhang, L., Martenyi, F., Lowe, S.L., Jackson, K.A., Andreev, B.V., Avedisova, A.S., Bardenstein, L.M., Gurovich, I.Y., Morozova, M.A., Mosolov, S.N., Neznanov, N.G., Reznik, A.M., Smulevich, A.B., Tochilov, V.A., Johnson, B.G., Monn, J.A., Schoepp, D.D., 2007. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nature Med 13, 1102-1107]. The endogenous neuropeptide N-acetylaspartylglutamate (NAAG) has been described as an agonist at mGluR2 and mGluR3 [Wroblewska, B., Wroblewski, J.T., Pshenichkin, S., Surin, A., Sullivan, S.E., Neale, J.H., 1997. N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J. Neurochem. 69, 174-181; Cartmell, J., Adam, G., Chaboz, S., Henningsen, R., Kemp, J.A., Klingelschmidt, A., Metzler, V., Monsma, F., Schaffhauser, H., Wichmann, J., Mutel, V., 1998. Characterization of [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes. Br. J. Pharmacol. 123, 497-504] and is degraded by the enzyme glutamate carboxypeptidase II (also known as N-acetyl-alpha-linked acidic dipeptidase or NAALADase). Hence, elevating the concentration of endogenous NAAG by inhibition of NAALADase represents a potential strategy for the treatment of schizophrenia via group II mGluR activation. We therefore investigated the activity of NAAG at both rat native and human recombinant mGluRs. We found that NAAG had no effect on synaptic transmission at the medial perforant pathway inputs to the rat dentate gyrus which is known to be sensitive to group II mGluR activation. We proceeded to examine the effects of NAAG at human recombinant mGluR2 and mGluR3 in a cellular G protein-activated K+ channel electrophysiology assay. Furthermore, due to discrepancies in the literature concerning the activity of NAAG at the N-methyl-d-aspartate receptor [NMDAR; Westbrook, G.L., Mayer, M.L., Namboodiri, M.A., Neale, J.H., 1986. High concentrations of N-acetylaspartylglutamate (NAAG) selectively activate NMDA receptors on mouse spinal cord neurons in cell culture. J. Neurosci. 6, 3385-3392; Losi, G., Vicini, S., Neale, J., 2004. NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons. Neuropharmacology 46, 490-496], we also tested NAAG at NMDARs in rat hippocampal neurons in culture. We found that a purified NAAG preparation had no effect at mGluR2, mGluR3 or NMDAR. Taken together, these findings do not support a rationale for targeting NAALADase and increasing extracellular NAAG levels as a therapeutic strategy for the treatment of schizophrenia.
机译：据报道，II型代谢型谷氨酸受体激动剂对精神分裂症的症状具有临床疗效[Patil，ST，Zhang，L.，Martenyi，F.，Lowe，SL，Jackson，KA，Andreev，BV，Avedisova， AS，Bardenstein，LM，Gurovich，IY，Morozova，MA，Mosolov，SN，Neznanov，NG，Reznik，AM，Smulevich，AB，Tochilov，VA，Johnson，BG，Monn，JA，Schoepp，DD，2007年。 mGlu2 / 3受体作为治疗精神分裂症的新方法：一项随机的2期临床试验。 Nature Med 13，1102-1107]。内源性神经肽N-乙酰天冬氨酰谷氨酸（NAAG）被描述为mGluR2和mGluR3的激动剂[Wroblewska，B.，Wroblewski，JT，Pshenichkin，S.，Surin，A.，Sullivan，SE，Neale，JH，1997。 -乙酰基天冬氨酰谷氨酸选择性激活转染细胞中的mGluR3受体。 J.神经化学。 69，174-181;卡特梅尔J.，亚当G.，查博斯S.，亨宁森R.，肯普K.JA，克林格尔施密特A.，梅茨勒V.，蒙斯玛F.沙夫豪瑟H.维奇曼J.穆特尔，V.，1998. [3H]-（2S，2'R，3'R）-2-（2'，3'-二羧基-环丙基）甘氨酸（[3H] -DCG IV）与亲代谢性mGlu2结合的表征受体转染的细胞膜。 Br。 J.Pharmacol。 123，497-504]，并被谷氨酸羧肽酶II（也称为N-乙酰基-α-连接的酸性二肽酶或NAALADase）降解。因此，通过抑制NAALADase提高内源性NAAG的浓度代表了通过II族mGluR活化治疗精神分裂症的潜在策略。因此，我们研究了NAAG对大鼠天然和人重组mGluRs的活性。我们发现NAAG对大鼠齿状回的内侧穿孔通路输入处的突触传递没有影响，已知该齿状回对II型mGluR激活敏感。我们着手在细胞G蛋白激活的K +通道电生理测定中检查NAAG对人重组mGluR2和mGluR3的影响。此外，由于文献中关于NAAG对N-甲基-d-天冬氨酸受体的活性的差异[NMDAR; Westbrook，G.L.，Mayer，ML。，Namboodiri，MA。，Neale，J.H.，1986。高浓度的N-乙酰天冬氨酰谷氨酸盐（NAAG）在细胞培养物中选择性激活小鼠脊髓神经元的NMDA受体。 J.神经科学。 6，3385-3392; Losi，G.，Vicini，S.，Neale，J.，2004。NAAG不能拮抗小脑颗粒神经元中的突触和突触外NMDA受体。 [Neuropharmacology 46，490-496]，我们还在培养的大鼠海马神经元中的NMDAR处测试了NAAG。我们发现纯化的NAAG制剂对mGluR2，mGluR3或NMDAR没有影响。综上所述，这些发现不支持针对NAALADase和增加细胞外NAAG水平作为治疗精神分裂症的治疗策略的理论依据。

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