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Upregulation of glutamate transporter GLT‐1 by mTOR‐Akt‐NF‐кB cascade in astrocytic oxygen‐glucose deprivation
Author(s) -
Ji YiFei,
Zhou Liang,
Xie YaJun,
Xu SiMin,
Zhu Jia,
Teng Peng,
Shao ChongYu,
Wang Yin,
Luo JianHong,
Shen Ying
Publication year - 2013
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22566
Subject(s) - pi3k/akt/mtor pathway , downregulation and upregulation , biology , protein kinase b , glucose transporter , glutamate receptor , excitatory amino acid transporter , astrocyte , transporter , neuroscience , microbiology and biotechnology , endocrinology , biochemistry , signal transduction , receptor , central nervous system , gene , insulin
Excessive extracellular glutamate leads to neuronal death in central nervous system. Excitatory glutamate transporter subtype 2 (GLT‐1) carries bulk of glutamate reuptake in cerebral ischemia. Although GLT‐1 expression fluctuates during the period of ischemia, little is known about its regulatory mechanism. Here we show an up‐regulation of GLT‐1 via mammalian target of rapamycin (mTOR)‐Akt‐nuclear factor‐кB (NF‐кB) signaling cascade in oxygen glucose deprivation (OGD). We found that brief rapamycin treatment significantly increased GLT‐1 expression in cultured astrocytes. Rapamycin increased phosphorylation of raptor at Ser792 and decreased phosphorylation of rictor at Thr1135, suggesting that both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) are involved in GLT‐1 expression. This conclusion was further confirmed by raptor and rictor disruption experiments. Akt was activated by mTORC1 inhibition and required for GLT‐1 expression because triciribine, a specific inhibitor of Akt, blocked the increase of GLT‐1 expression. mTOR‐Akt cascade then activated NF‐кB and increased кB‐motif‐binding phosphoprotein (KBBP) expression and GLT‐1 transcription. We next demonstrated that mTOR‐Akt‐NF‐кB cascade was activated in OGD and subsequently caused the upregulation of GLT‐1. Supporting evidence included: (1) inhibition of Akt or NF‐кB occluded OGD‐induced GLT‐1 upregulation; (2) Raptor knock‐down plus OGD did not add to the increase of GLT‐1 expression; (3) Intact mTORC2 was required for GLT‐1 enhancement. In summary, our data first showed that mTOR‐Akt‐NF‐кB cascade played critical roles to up‐regulate GLT‐1 in OGD. This signaling cascade may work to promote glutamate uptake in brain ischemia and neurodegenerative diseases. GLIA 2013;61:1959–1975