PT  - JOURNAL ARTICLE
AU  - Zelenaia, Olga
AU  - Schlag, Brian D.
AU  - Gochenauer, Gordon E.
AU  - Ganel, Raquelli
AU  - Song, Wei
AU  - Beesley, Jacqueline S.
AU  - Grinspan, Judith B.
AU  - Rothstein, Jeffrey D.
AU  - Robinson, Michael B.
TI  - Epidermal Growth Factor Receptor Agonists Increase Expression of Glutamate Transporter GLT-1 in Astrocytes through Pathways Dependent on Phosphatidylinositol 3-Kinase and Transcription Factor NF-κB
AID  - 10.1124/mol.57.4.667
DP  - 2000 Apr 01
TA  - Molecular Pharmacology
PG  - 667--678
VI  - 57
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/57/4/667.short
4100  - http://molpharm.aspetjournals.org/content/57/4/667.full
SO  - Mol Pharmacol2000 Apr 01; 57
AB  - The glial glutamate transporter GLT-1 may be the predominant Na+-dependent glutamate transporter in forebrain. Expression of GLT-1 correlates with astrocyte maturation in vivo and increases during synaptogenesis. In astrocyte cultures, GLT-1 expression parallels differentiation induced by cAMP analogs or by coculturing with neurons. Molecule(s) secreted by neuronal cultures contribute to this induction of GLT-1, but little is known about the signaling pathways mediating this regulation. In the present study, we determined whether growth factors previously implicated in astrocyte differentiation regulate GLT-1 expression. Of the six growth factors tested, two [epidermal growth factor (EGF) and transforming growth factor-α] induced expression of GLT-1 protein in cultured astrocytes. Induction of GLT-1 protein was accompanied by an increase in mRNA and in the V max for Na+-dependent glutamate transport activity. The effects of dibutyryl-cAMP and EGF were additive but were independently blocked by inhibitors of protein kinase A or protein tyrosine kinases, respectively. The induction of GLT-1 in both EGF- and dibutyryl-cAMP-treated astrocytes was blocked by inhibitors targeting phosphatidylinositol 3-kinase (PI3K) or the nuclear transcription factor-κB. Furthermore, transient transfection of astrocyte cultures with a constitutively active PI3K construct was sufficient to induce expression of GLT-1. These data suggest that independent but converging pathways mediate expression of GLT-1. Although an EGF receptor-specific antagonist did not block the effects of neuron-conditioned medium, the induction of GLT-1 by neuron-conditioned medium was completely abolished by inhibition of PI3K or nuclear factor-κB. EGF also increased expression of GLT-1 in spinal cord organotypic cultures. Together, these data suggest that activation of specific signaling pathways with EGF-like molecules may provide a novel approach for limiting excitotoxic brain injury.