A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke

Judith Mallolas, Olivia Hurtado, Mar Castellanos, Miguel Blanco, Tomás Sobrino, Joaquín Serena, José Vivancos, José Castillo, Ignacio Lizasoain, María A. Moro, Antoni Dávalos

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    79 Citations (Scopus)

    Abstract

    It remains unclear why some individuals are susceptible to excitotoxicity after stroke. A possible explanation is impaired glutamate uptake. We have found a highly prevalent polymorphism in the promoter of the glutamate transporter EAAT2 gene that abolishes a putative regulatory site for activator protein-2 (AP-2) and creates a new consensus binding site for the repressor transcription factor GC-binding factor 2 (GCF2). The mutant genotype is associated with increased plasma glutamate concentrations and with a higher frequency of early neurological worsening in human stroke. After transfection into astrocytes, the mutant promoter was not activated by AP-2 and was effectively repressed by GCF2, and its activity in the presence of GCF2 was reduced when compared with the AP-2-cotransfected wild-type promoter. We also show that GCF2 is expressed in ischemic rat brain, suggesting that decreased glutamate uptake occurs in individuals carrying the mutation after stroke. These findings may explain individual susceptibility to excitotoxic damage after stroke as well as the failure of glutamate antagonists in those patients without this polymorphism. JEM © The Rockefeller University Press.
    Original languageEnglish
    Pages (from-to)711-717
    JournalJournal of Experimental Medicine
    Volume203
    Issue number3
    DOIs
    Publication statusPublished - 20 Mar 2006

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