title: Glutamine synthetase down-regulation reduces astrocyte protection against glutamate excitotoxicity to neurons.
abstract: 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.
authors.affiliation: Department of Neurobiology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Wang
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Dou
authors.forename: He-Zuo
authors.initials: HZ
authors.lastname: Lü
authors.forename: Zheng-Wen
authors.initials: ZW
authors.lastname: Ma
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Lu
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001253:Astrocytes / Q000502:physiology*; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D018846:Excitatory Amino Acids / Q000633:toxicity*; D005974:Glutamate-Ammonia Ligase / Q000235:genetics / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity*; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D018846:Excitatory Amino Acids; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D005974:Glutamate-Ammonia Ligase