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首页> 外文期刊>Journal of Cellular Physiology >Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics.
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Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics.

机译：兴奋性氨基酸transporter-2的角色(EAAT2)和谷氨酸神经退化:开发新的疗法的机会。

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Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Analysis of the 2.5 kb human EAAT2 promoter showed that NF-kappaB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many beta-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a beta-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes through the NF-kappaB signaling pathway. The NF-kappaB binding site at -272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration.
机译：谷氨酸是一个重要的兴奋性神经递质调节大脑功能。兴奋性氨基酸转运蛋白2 (EAAT)就是其中之一主要的谷氨酸转运蛋白表达主要在astroglial细胞负责谷氨酸摄取总量的90%。谷氨酸转运蛋白谷氨酸进行严格的检查浓度在突触间隙。过度的EAAT2和积累细胞外谷氨酸被卷入一些神经退行性的发展疾病,包括阿尔茨海默病,亨廷顿氏病和肌萎缩性脊髓侧索硬化。子显示NF-kappaB是重要的监管机构的EAAT2星形胶质细胞中表达。筛选约1040 fda批准化合物和营养品发现许多beta-lactam抗生素转录激活物EAAT2导致EAAT2蛋白质含量增加。beta-lactam动物与头孢曲松(CEF)抗生素,导致增加EAAT2表达和谷氨酸运输活动大脑。体外和体内模型都基于它能够抑制神经细胞的死亡防止谷氨酸会引起。增加EAAT2转录在主要的人类胎儿通过NF-kappaB星形胶质细胞信号途径。位置是关键CEF-mediated EAAT2蛋白质的感应。转录调节的重要性大脑中控制谷氨酸水平。也强调了EAAT2的潜在效用启动子开发低和高通量筛选化验确定小说小分子监管者谷氨酸运输改善病理变化与潜力期间发生,造成神经退化。

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