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Excitotoxicity through Ca2+ -permeable AMPA receptors requires Ca2+ -dependent JNK activation

Abstract The GluA4-containing Ca2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (Ca-AMPARs) were previously shown to mediate excitotoxicity through mechanisms involving the activator protein-1 (AP-1), a c-Jun N-terminal kinase (JNK) substrate. To further investigate JNK...

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Published in:Neurobiology of disease 2010-12, Vol.40 (3), p.645-655
Main Authors: Vieira, M, Fernandes, J, Burgeiro, A, Thomas, G.M, Huganir, R.L, Duarte, C.B, Carvalho, A.L, Santos, A.E
Format: Article
Language:English
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Summary:Abstract The GluA4-containing Ca2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (Ca-AMPARs) were previously shown to mediate excitotoxicity through mechanisms involving the activator protein-1 (AP-1), a c-Jun N-terminal kinase (JNK) substrate. To further investigate JNK involvement in excitotoxic pathways coupled to Ca-AMPARs we used HEK293 cells expressing GluA4-containing Ca-AMPARs (HEK-GluA4). Cell death induced by overstimulation of Ca-AMPARs was mediated, at least in part, by JNK. Importantly, JNK activation downstream of these receptors was dependent on the extracellular Ca2+ concentration. In our quest for a molecular link between Ca-AMPARs and the JNK pathway we found that the JNK interacting protein-1 (JIP-1) interacts with the GluA4 subunit of AMPARs through the N-terminal domain. In vivo , the excitotoxin kainate promoted the association between GluA4 and JIP-1 in the rat hippocampus. Taken together, our results show that the JNK pathway is activated by Ca-AMPARs upon excitotoxic stimulation and suggest that JIP-1 may contribute to the propagation of the excitotoxic signal.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2010.08.008