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NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?

机译:NMDA受体介导的N-乙酰天门冬氨酸外排:生理和/或病理学重要性?

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N-Acetylaspartate (NAA) is a largely neuron specific dianionic amino acid present in high concentration in vertebrate brain. Many fundamental questions concerning N-acetylaspartate in brain remain unanswered. One such issue is the predominantly neuronal synthesis and largely glial catabolism which implies the existence of a regulated efflux from neurons. Here we show that transient (5 min) NMDA-receptor activation (60 microM) induces a long lasting Ca2+ -dependent efflux of N-acetylaspartate from organotypic slices of rat hippocampus. The NMDA-receptor stimulated efflux was unaffected by hyper-osmotic conditions (120 mM sucrose) and no efflux of N-acetylaspartate was evoked by high K+ -depolarization (50 mM) or kainate (300 microM). These results indicate that the efflux induced by NMDA is not related directly to either cell swelling or depolarization but is coupled to Ca2+ -influx via the NMDA-receptor. The efflux of N-acetylaspartate persisted at least 20 min after the omission of NMDA, similar to the efflux of the organic anions glutathione and phosphoethanolamine. The efflux of taurine and hypotaurine was also stimulated by NMDA but returned more quickly to basal levels. The NMDA-receptor stimulated efflux of N-acetylaspartate, glutathione, phosphoethanolamine, taurine and hypotaurine correlated with delayed nerve cell death measured 24 h after the transient NMDA-receptor stimulation. However, exogenous administration of high concentrations of N-acetylaspartate to the culture medium was non-toxic. The results suggest that Ca2+ -influx via the NMDA-receptor regulates the efflux of N-acetylaspartate from neurons which may have both physiological and pathological importance.
机译:N-乙酰乙酰天冬氨酸(NAA)是在脊椎动物脑中高浓度存在的主要神经元特异性双阴离子氨基酸。关于脑中N-乙酰天门冬氨酸的许多基本问题仍未得到解答。这样的问题之一是主要是神经元合成和神经胶质分解代谢,这意味着存在神经元调节的外排。在这里,我们显示瞬时(5分钟)NMDA受体激活(60 microM)诱导大鼠海马器官型切片的N-乙酰天冬氨酸的持久Ca2 +依赖性外排。 NMDA受体刺激的流出不受高渗条件(120 mM蔗糖)的影响,并且高K +去极化(50 mM)或海藻酸盐(300 microM)不会引起N-乙酰天门冬氨酸的流出。这些结果表明,由NMDA诱导的外排与细胞膨胀或去极化均不直接相关,而是通过NMDA受体与Ca 2+-内流耦合。 N-乙酰天门冬氨酸的流出至少在NMDA后至少20分钟持续,类似于有机阴离子谷胱甘肽和磷酸乙醇胺的流出。 NMDA也刺激牛磺酸和次牛磺酸的流出,但恢复到基础水平的速度更快。 NMDA受体刺激N-乙酰天门冬氨酸,谷胱甘肽,磷酸乙醇胺,牛磺酸和低牛磺酸的流出与瞬时NMDA受体刺激后24小时测得的神经细胞死亡延迟有关。但是,向培养基中外源施用高浓度的N-乙酰天门冬氨酸是无毒的。结果表明,Ca2 +通过NMDA受体流入可调节N-乙酰天门冬氨酸从神经元的流出,这可能具有生理和病理学意义。

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