Original Paper
Cell Death and Differentiation (2006) 13, 652–660. doi:10.1038/sj.cdd.4401785; published online 11 November 2005
Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor
Edited by P Nicotera
A E Santos1,2, C B Duarte1, M Iizuka3, E L Barsoumian3, J Ham4, M C Lopes1,2, A P Carvalho1 and A L Carvalho1
- 1Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal
- 2Faculty of Pharmacy, University of Coimbra, 3004-517 Coimbra, Portugal
- 3Department of Molecular and Cellular Biology, Nippon Boehringer Ingelheim Co., Ltd, Kawanishi Pharma Research Institute, 3-10-1, Yato, Kawanishi 666-0193 Japan
- 4Molecular Haematology and Cancer Biology Unit, Camelia Botnar Laboratories, Institute of Child Health, University College London, London WC1N 1EH, UK
Correspondence: AL Carvalho, Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-514 Coimbra, Portugal. Tel: +351-239-480210; Fax: +351-239-480208; E-mail: alc@imagem.ibili.uc.pt
Received 7 June 2005; Revised 2 August 2005; Accepted 11 August 2005; Published online 11 November 2005.
Abstract
Cells preferentially expressing GluR4-containing 
-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors are particularly sensitive to excitotoxicity mediated through non-N-methyl-D-aspartate receptors. However, the excitotoxic signalling pathways associated with GluR4-containing AMPA receptors are not known. In this work, we investigated the downstream signals coupled to excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors, using a HEK 293 cell line constitutively expressing the GluR4flip subunit of AMPA receptors (HEK-GluR4). Glutamate stimulation of GluR4-containing AMPA receptors decreased cell viability, in a calcium-dependent manner, when the receptor desensitisation was prevented with cyclothiazide. The excitotoxic stimulation mediated through GluR4-containing AMPA receptors increased activator protein-1 (AP-1) DNA-binding activity. Inhibition of the AP-1 activity by overexpression of a c-Jun dominant-negative form protected HEK-GluR4 cells against excitotoxic damage. Taken together, the results indicate that overactivation of Ca2+-permeable GluR4-containing AMPA receptors is coupled to a death pathway mediated, at least in part, by the AP-1 transcription factor.
Keywords:
excitotoxicity, glutamate, Ca2+-permeable AMPA receptors, GluR4 subunit, activator protein-1 (AP-1) transcription factor
Abbreviations:
HEK, human embrionic kidney; AMPA, -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; KA, kainate; NMDA, N-methyl-D-aspartate; GluR, glutamate receptor; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; CTZ, cyclothiazide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl Tetrazolium bromide; PBS, phosphate buffered saline; AP-1, activator protein-1; dn c-Jun, c-Jun dominant negative; JNK, c-Jun N-terminal kinase; MLK, mixed lineage kinase; ATF2, activating transcription factor 2; PSD, postsynaptic density; ALS, amyotrophic lateral sclerosis
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