Abstract:
: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.
journal_name
Gliajournal_title
Gliaauthors
Ji YF,Zhou L,Xie YJ,Xu SM,Zhu J,Teng P,Shao CY,Wang Y,Luo JH,Shen Ydoi
10.1002/glia.22566subject
Has Abstractpub_date
2013-12-01 00:00:00pages
1959-75issue
12eissn
0894-1491issn
1098-1136journal_volume
61pub_type
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