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

The Journal of Experimental Medicine
Judith MallolasAntoni Dávalos

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.

References

Jan 1, 1990·Annual Review of Neuroscience·D W Choi, S M Rothman
Feb 1, 1986·Annals of Neurology·S M Rothman, J W Olney
Dec 14, 1995·The New England Journal of Medicine·UNKNOWN National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
Mar 3, 1994·The New England Journal of Medicine·S A Lipton, P A Rosenberg
May 11, 1994·Biochimica Et Biophysica Acta·P ShashidharanA Plaitakis
Jun 1, 1996·Stroke; a Journal of Cerebral Circulation·J CastilloM Noya
Apr 1, 1997·Stroke; a Journal of Cerebral Circulation·A DávalosM Noya
Aug 1, 1997·Journal of Neuropathology and Experimental Neurology·S LiE Masliah
Aug 15, 1998·The Journal of Biological Chemistry·A L ReedA C Johnson
May 20, 1999·Annual Review of Pharmacology and Toxicology·R P Seal, S G Amara
Jun 5, 1999·Molecular Genetics and Metabolism·J MallolasM A Vilaseca
Jul 13, 1999·Neuroscience Research·M ShimadaT Tamura
May 23, 2001·Progress in Neurobiology·N C Danbolt
Sep 8, 2001·Progress in Brain Research·G GegelashviliT Rauen
Feb 13, 2003·Proceedings of the National Academy of Sciences of the United States of America·Zao-zhong SuPaul B Fisher
Sep 23, 2003·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Olivia HurtadoMaría A Moro
Oct 3, 2003·Biochimica Et Biophysica Acta·Toshiki RikiyamaAlfred C Johnson
Oct 31, 2003·Cerebrovascular Diseases·UNKNOWN European Stroke Initiative Executive CommitteePhilip Bath
Feb 13, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Cristina RomeraMaria A Moro
Apr 2, 2004·Neurobiology of Disease·Nicholas J Maragakis, Jeffrey D Rothstein

❮ Previous
Next ❯

Citations

Nov 23, 2006·Nature Clinical Practice. Neurology·Nicholas J Maragakis, Jeffrey D Rothstein
Feb 20, 2008·The Journal of Experimental Medicine·Craig N MorrellCharles J Lowenstein
Mar 25, 2009·Antioxidants & Redox Signaling·Silvia Sorce, Karl-Heinz Krause
Jan 11, 2007·Cephalalgia : an International Journal of Headache·M VaccaroC Ferrarese
Nov 26, 2010·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Rachel ArakawaKathleen E Sullivan
May 3, 2006·Cerebrovascular Diseases·I LizasoainM A Moro
Sep 4, 2013·The Journal of Clinical Investigation·María del Carmen GodinoJosé Sánchez-Prieto
May 29, 2010·Neurology India·Anjana Munshi, Subhash Kaul
Oct 1, 2013·European Psychiatry : the Journal of the Association of European Psychiatrists·S PolettiF Benedetti
Apr 1, 2014·Acta Pharmacologica Sinica·Weronika KrzyżanowskaJoanna Pera
Jun 24, 2014·Pharmacogenomics·Marco SpangaroRoberto Cavallaro
Feb 13, 2014·Progress in Neuro-psychopharmacology & Biological Psychiatry·Sara PolettiFrancesco Benedetti
Jun 26, 2012·Neuroscience Letters·Marco SpangaroRoberto Cavallaro
Jul 20, 2010·Progress in Neuro-psychopharmacology & Biological Psychiatry·Hua-Lin CaiHai-Sen Ye
Dec 18, 2015·BBA Clinical·Eva TerniMichelangelo Mancuso
Nov 28, 2009·Brain Research Bulletin·Eduardo Pacheco RicoMaurício Reis Bogo
May 23, 2007·Neurochemistry International·Amanda L Sheldon, Michael B Robinson
Jan 24, 2007·Lancet Neurology·Martin Dichgans
Nov 8, 2006·British Journal of Pharmacology·P M Beart, R D O'Shea
Dec 9, 2010·International Journal of Cancer. Journal International Du Cancer·Hideo OhtsukaAlfred C Johnson
Apr 29, 2010·British Journal of Pharmacology·S SorceK H Krause
Dec 21, 2013·British Journal of Clinical Pharmacology·Gavin P ReynoldsCaroline F Dalton
Jun 10, 2015·Translational Psychiatry·S M O'DonovanR E McCullumsmith
Oct 20, 2006·Neuroscience·R Káradóttir, D Attwell
Mar 8, 2013·Neurología : publicación oficial de la Sociedad Española de Neurología·T Guillamón-VivancosJ Matías-Guiu
Jan 11, 2007·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Cristina RomeraMaria A Moro
Apr 13, 2018·International Journal of Molecular Sciences·Mariko Kato Hayashi
Jan 6, 2007·Stroke; a Journal of Cerebral Circulation·Martin Dichgans, Robert A Hegele
Mar 8, 2008·Stroke; a Journal of Cerebral Circulation·Jovita PonceTeresa Gasull
Nov 29, 2007·Cerebrovascular Diseases·Natalia Pérez de la Ossa, Antoni Dávalos

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
transfection

Software Mentioned

SPSS

Related Concepts

Related Feeds

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.