Published online 6 March 2006 doi:10.1084/jem.20051979
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 3, 711-717
A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke
Judith Mallolas1,
Olivia Hurtado2,
Mar Castellanos1,
Miguel Blanco4,
Tomás Sobrino4,
Joaquín Serena1,
José Vivancos3,
José Castillo4,
Ignacio Lizasoain2,
María A. Moro2, and
Antoni Dávalos5
1 Department of Neurology, Hospital Universitario Doctor Josep Trueta, 17007 Girona, Spain
2 Department of Pharmacology, School of Medicine, University Complutense de Madrid, 28040 Madrid, Spain
3 Department of Neurology, Hospital Universitario La Princesa, 28006 Madrid, Spain
4 Department of Neurology, Hospital Clínico Universitario, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain
5 Department of Neurosciences, Hospital Universitario Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
CORRESPONDENCE María A. Moro: neurona{at}med.ucm.es OR Antoni Dávalos: adavalos.germanstrias{at}gencat.net
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.
Abbreviations used: AP-2, activator protein–2; CSF, cerebrospinal fluid; GCF2, GC-binding factor 2; MCAO, middle cerebral artery occlusion; SSCP, single-strand conformation polymorphism.
M.A. Moro and A. Dávalos contributed equally to this work.
J. Mallolas and O. Hurtado contributed equally to this work.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
Related Article
-
Dying of excitement
- Heather L. Van Epps
J. Exp. Med. 2006 203: 484a.
[Full Text]
[PDF]
This article has been cited by other articles:
-
Sama, M. A., Mathis, D. M., Furman, J. L., Abdul, H. M., Artiushin, I. A., Kraner, S. D., Norris, C. M.
(2008). Interleukin-1{beta}-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity. J. Biol. Chem.
283: 21953-21964
[Abstract]
[Full Text]
-
Ponce, J., de la Ossa, N. P., Hurtado, O., Millan, M., Arenillas, J. F., Davalos, A., Gasull, T.
(2008). Simvastatin Reduces the Association of NMDA Receptors to Lipid Rafts: A Cholesterol-Mediated Effect in Neuroprotection. Stroke
39: 1269-1275
[Abstract]
[Full Text]
-
Morrell, C. N., Sun, H., Ikeda, M., Beique, J.-C., Swaim, A. M., Mason, E., Martin, T. V., Thompson, L. E., Gozen, O., Ampagoomian, D., Sprengel, R., Rothstein, J., Faraday, N., Huganir, R., Lowenstein, C. J.
(2008). Glutamate mediates platelet activation through the AMPA receptor. J. Exp. Med.
205: 575-584
[Abstract]
[Full Text]
-
Dichgans, M., Hegele, R. A.
(2007). Update on the Genetics of Stroke and Cerebrovascular Disease 2006. Stroke
38: 216-218
[Full Text]
