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Upregulation of glutamate transporter GLT-1 by mTOR-Akt-NF-small ka, CyrillicB cascade in astrocytic oxygen-glucose deprivation.

Authors: Ji, YF  Zhou, L  Xie, YJ  Xu, SM  Zhu, J  Teng, P  Shao, CY  Wang, Y  Luo, JH  Shen, Y 
Citation: Ji YF, etal., Glia. 2013 Dec;61(12):1959-75. doi: 10.1002/glia.22566. Epub 2013 Sep 24.
Pubmed: (View Article at PubMed) PMID:24108520
DOI: Full-text: DOI:10.1002/glia.22566

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-small ka, CyrillicB (NF-small ka, CyrillicB) 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-small ka, CyrillicB and increased small ka, CyrillicB-motif-binding phosphoprotein (KBBP) expression and GLT-1 transcription. We next demonstrated that mTOR-Akt-NF-small ka, CyrillicB cascade was activated in OGD and subsequently caused the upregulation of GLT-1. Supporting evidence included: (1) inhibition of Akt or NF-small ka, CyrillicB 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-small ka, CyrillicB 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.

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CRRD Object Information
CRRD ID: 10058979
Created: 2015-08-11
Species: All species
Last Modified: 2015-08-11
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.