title: A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke.
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.
authors.affiliation: Department of Neurology, Hospital Universitario Doctor Josep Trueta, 17007 Girona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Mallolas
authors.forename: Olivia
authors.initials: O
authors.lastname: Hurtado
authors.forename: Mar
authors.initials: M
authors.lastname: Castellanos
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanco
authors.forename: Tomás
authors.initials: T
authors.lastname: Sobrino
authors.forename: Joaquín
authors.initials: J
authors.lastname: Serena
authors.forename: José
authors.initials: J
authors.lastname: Vivancos
authors.forename: José
authors.initials: J
authors.lastname: Castillo
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lizasoain
authors.forename: María A
authors.initials: MA
authors.lastname: Moro
authors.forename: Antoni
authors.initials: A
authors.lastname: Dávalos
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001692:Biological Transport / Q000235:genetics; D001923:Brain Chemistry / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D018698:Glutamic Acid / Q000097:blood / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D020521:Stroke / Q000097:blood / Q000235:genetics*; D050656:Transcription Factor AP-2 / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C114370:LRRFIP1 protein, human; D016601:RNA-Binding Proteins; C493397:SLC1A2 protein, human; D050656:Transcription Factor AP-2; D018698:Glutamic Acid