A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke.
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.
Mallolas
Judith
J
Department of Neurology, Hospital Universitario Doctor Josep Trueta, 17007 Girona, Spain.
Hurtado
Olivia
O
Castellanos
Mar
M
Blanco
Miguel
M
Sobrino
Tomás
T
Serena
Joaquín
J
Vivancos
José
J
Castillo
José
J
Lizasoain
Ignacio
I
Moro
María A
MA
Dávalos
Antoni
A
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
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