Regulation of astrocytic glutamate transporter expression by Akt: Evidence for a selective transcriptional effect on the GLT-1/EAAT2 subtype

Li Bin Li, Shuy Vang Toan, Olga Zelenaia, Deborah J. Watson, John H. Wolfe, Jeffrey D. Rothstein, Michael B. Robinson

Research output: Contribution to journalArticlepeer-review

Abstract

In the nervous system, astrocytes express different ratios of the two glial glutamate transporters, glutamate transporter subtype 1 (GLT-1) and glutamate/aspartate transporter (GLAST), but little is known about the signaling pathways that independently regulate their expression. Treatment with dibutyryl-cAMP, epidermal growth factor (EGF) or other growth factors both induces expression of GLT-1 and increases expression of GLAST in astrocyte cultures. The induction of GLT-1 is correlated with morphological and biochemical changes that are consistent with astrocyte maturation. Pharmacological studies suggest that phosphatidylinositol 3-kinase (PI-3K) and the nuclear transcription factor-κB (NF-κB) may be involved in the induction of GLT-1 expression. In several signaling systems Akt, also known as protein kinase B (PKB), functions downstream of PI-3K. In these present studies we used lentiviral vectors engineered to express dominant-negative (DN), constitutively active (CA), or null variants of Akt to study the possible involvement of Akt in the regulation of GLT-1. Expression of DN-Akt attenuated the EGF-dependent induction of GLT-1. Expression of CA-Akt caused a dose- and time-dependent increase in GLT-1 protein, increased GLT-1 mRNA levels, increased dihydrokainate-sensitive (presumably GLT-1 mediated) transport activity, and caused a change in astrocyte morphology to a more stellate shape, but had no effect on GLAST protein levels. Finally, the expression of CA-Akt increased the expression of a reporter construct containing a putative promoter fragment from the human homolog of GLT-1, called EAAT2. From these studies, we conclude that Akt induces the expression of GLT-1 through increased transcription and that Akt can regulate GLT-1 expression without increasing GLAST expression in astrocytes.

Original languageEnglish (US)
Pages (from-to)759-771
Number of pages13
JournalJournal of Neurochemistry
Volume97
Issue number3
DOIs
StatePublished - May 2006

Keywords

  • GLAST
  • GLT-1
  • Glutamate
  • Rkt
  • Transport

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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