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Molecular Pharmacology

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Research ArticleArticle

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

Olga Zelenaia, Brian D. Schlag, Gordon E. Gochenauer, Raquelli Ganel, Wei Song, Jacqueline S. Beesley, Judith B. Grinspan, Jeffrey D. Rothstein and Michael B. Robinson
Molecular Pharmacology April 2000, 57 (4) 667-678; DOI: https://doi.org/10.1124/mol.57.4.667
Olga Zelenaia
Departments of 1 2 3 4
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Brian D. Schlag
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Gordon E. Gochenauer
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Raquelli Ganel
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Wei Song
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Jacqueline S. Beesley
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Judith B. Grinspan
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Jeffrey D. Rothstein
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Michael B. Robinson
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Abstract

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.

Footnotes

    • Received November 11, 1999.
    • Accepted January 3, 2000.
  • Send reprint requests to: Dr. Michael B. Robinson, 502N Abramson Pediatric Research Building, 34th and Civic Center Blvd., Philadelphia, PA 19104-4318. E-mail: Robinson{at}pharm.med.upenn.edu

  • ↵1 O.Z. and B.D.S. contributed equally to the present study.

  • This study was supported by Grants NS29868 and HD26979 (to M.B.R), NS33958 (to J.D.R.), NS36465 (to M.B.R. and J.D.R.), and NS34017 (to J.B.G.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (4)
Molecular Pharmacology
Vol. 57, Issue 4
1 Apr 2000
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Research ArticleArticle

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

Olga Zelenaia, Brian D. Schlag, Gordon E. Gochenauer, Raquelli Ganel, Wei Song, Jacqueline S. Beesley, Judith B. Grinspan, Jeffrey D. Rothstein and Michael B. Robinson
Molecular Pharmacology April 1, 2000, 57 (4) 667-678; DOI: https://doi.org/10.1124/mol.57.4.667

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Research ArticleArticle

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

Olga Zelenaia, Brian D. Schlag, Gordon E. Gochenauer, Raquelli Ganel, Wei Song, Jacqueline S. Beesley, Judith B. Grinspan, Jeffrey D. Rothstein and Michael B. Robinson
Molecular Pharmacology April 1, 2000, 57 (4) 667-678; DOI: https://doi.org/10.1124/mol.57.4.667
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