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Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM

Authors

  • Ylva Edling,

    Corresponding author
    1. Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
    • Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
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  • Magnus Ingelman-Sundberg,

    1. Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
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  • Anastasia Simi

    1. Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
    Current affiliation:
    1. Research Division of Neurosciences, Faculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UK
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Abstract

Activation of c-fos in brain is related to coupling of neuronal activity to gene expression, but also to pathological conditions such as seizures or excitotoxicity-induced cell death. Glutamate activates c-fos in neurons through the calcium-dependent phosphorylation of CREB by ERK and/or CaMKIV kinase pathways downstream NMDA-receptors. In glial cells, however, the activation of c-fos by glutamate is poorly understood. Because glial cells actively modulate neuronal excitability and the brain's response to injury, we studied the mechanisms by which glutamate activates c-fos in rat cortical glial cells. Glutamate potently induced c-fos mRNA in a calcium-dependent manner, as demonstrated by using the calcium chelator BAPTA-AM. Glutamate-induced c-fos mRNA expression was not sensitive to inhibitors of ERK, p38MAPK, or CaMK pathways, indicating that glial c-fos is activated by a distinct mechanism. Thapsigargin abolished the glutamate effect on c-fos mRNA, indicating ER calcium mobilization. Additionally, glutamate induction of c-fos mRNA was sensitive to the mGluR5 antagonist MPEP but not the NMDA-R antagonist MK-801. In luciferase reporter assays, DRE, which actively represses c-fos by binding the calcium-binding transcriptional repressor DREAM, was activated by glutamate, whereas SRE and CRE were not. Finally, glutamate caused the nuclear export of DREAM in astrocytes, and transfection of astrocytes with a mutant variant of DREAM that constitutively binds DNA inhibited glutamate-induced c-Fos expression. These findings are in sharp contrast to the mechanism described in neurons and suggest a novel pathway activated by glutamate in glial cells that employs mGluR5, ER calcium, and the derepression of c-fos at the DRE. © 2006 Wiley-Liss, Inc.

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