Department of Neurobiology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China.
Neurochem Int. 2010 Mar;56(4):577-84. doi: 10.1016/j.neuint.2009.12.021. Epub 2010 Jan 12.
Although the role of astrocyte glutamate transporters in glutamate clearance is well illustrated, the role of glutamine synthetase (GS) that influences this process remains to be elucidated. We examined whether GS affected the uptake of glutamate in astrocytes in vitro. The glutamate uptake was assessed by measuring the concentration of glutamate and glutamine in culture medium in the presence or absence of glutamate. We demonstrated that inhibition of GS in astrocytes by MSO significantly impaired glutamate uptake and glutamine release. Conversely, induction of GS expression in astrocytes by gene transfer significantly enhanced the glutamate uptake and glutamine release. When an inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was applied to the cultures, it significantly reduced GS expression and inhibited glutamate-induced GS activation resulting in increased excitotoxicity to neurons. These results suggest that GS in astrocytes may represent a novel target for neuroprotection against neuronal dysfunction and death that occur in many neurological disorders.
尽管星形胶质细胞谷氨酸转运体在谷氨酸清除中的作用已经得到很好的阐明，但影响这一过程的谷氨酰胺合成酶（GS）的作用仍有待阐明。我们研究了 GS 是否会影响体外星形胶质细胞中谷氨酸的摄取。通过在存在或不存在谷氨酸的情况下测量培养基中谷氨酸和谷氨酰胺的浓度来评估谷氨酸摄取。我们证明，用 MSO 抑制星形胶质细胞中的 GS 会显著损害谷氨酸摄取和谷氨酰胺释放。相反，通过基因转移诱导星形胶质细胞中 GS 的表达会显著增强谷氨酸摄取和谷氨酰胺释放。当将炎症细胞因子肿瘤坏死因子-α（TNF-α）施加到培养物上时，它会显著降低 GS 的表达并抑制谷氨酸诱导的 GS 激活，从而导致神经元的兴奋性毒性增加。这些结果表明，星形胶质细胞中的 GS 可能成为针对许多神经疾病中发生的神经元功能障碍和死亡的神经保护的新靶标。
