Ca2+-dependent reduction of glutamate aspartate transporter GLAST expression in astrocytes by P2X7 receptor-mediated phosphoinositide 3-kinase signaling

Yu Peng Liu, Chung Shi Yang, Mei Chun Chen, Synthia H. Sun, Shun Fen Tzeng

研究成果: Article同行評審

24 引文 斯高帕斯(Scopus)

摘要

Astrocytes are responsible for clearance of extracellular glutamate, primarily through glial-specific glutamate transporter-1 and the Na +-dependent glutamate/aspartate transporter (GLAST). After traumatic injury to the CNS, such as spinal cord injury, persistent release of ATP from damaged neurons and activated glial cells occurs, inducing detrimental and/or beneficial effects via activation of ionotropic (P2XR) and metabotropic purinergic receptors. In this study, we show a decrease in GLAST mRNA in the lesion center and caudal portions at 24 h post-spinal cord injury. In an in vitro system, the ability of astrocytes to take up glutamate and astrocytic GLAST mRNA levels were significantly decreased after exposure to ATP and its P2X7R agonist, 2′-3′-O-(4-benzoylbenzoyl)-ATP. ATP- or 2′-3′-O-(4-benzoylbenzoyl)-ATP-induced inhibitory effect on GLAST mRNA expression was blocked by the irreversible P2X7R blocker, oxidized ATP, or when P2X7R mRNA expression was reduced by the lentivirus-short hairpin RNA knockdown approach. Furthermore, deletion of the GLAST promoter and RNA decay assays showed that P2X7R signaling triggered post-transcriptional regulation of GLAST expression via the phosphoinositide 3-kinase cascade. The signaling pathway participating in the P2X7R effect on GLAST mRNA expression was identified as a Ca 2+-dependent phosphoinositide 3-kinase-phospholipase Cγ involving the inositol 1,4,5-trisphosphate receptor, calcium/calmodulin- dependent kinase II, and protein kinase C. We conclude that P2X7R activation by sustained release of ATP in the injured CNS may decrease GLAST mRNA stability via Ca2+-dependent signaling, suggesting that inhibition of P2X7R may allow for recovery of astrocytic GLAST function and protect neurons from glutamate-induced excitotoxicity.

原文English
頁(從 - 到)213-227
頁數15
期刊Journal of Neurochemistry
113
發行號1
DOIs
出版狀態Published - 2010 四月

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 細胞與分子神經科學

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