Glutamine synthetase down-regulation reduces astrocyte protection against glutamate excitotoxicity to neurons.
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.
Zou
Jian
J
Department of Neurobiology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, PR China.
Wang
Yan-Xia
YX
Dou
Fang-Fang
FF
Lü
He-Zuo
HZ
Ma
Zheng-Wen
ZW
Lu
Pei-Hua
PH
Xu
Xiao-Ming
XM
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
D018846:Excitatory Amino Acids; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D005974:Glutamate-Ammonia Ligase