期刊
NEUROBIOLOGY OF DISEASE
卷 40, 期 3, 页码 645-655出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2010.08.008
关键词
AMPA receptors; AP-1 transcription factor; Calcium channels; Cell death; Excitotoxicity; Transient global ischemia; JNK
资金
- Biogen Idec Portugal
- Fundacao para a Ciencia e Tecnologia (FCT) [PTDC/BIA-BCM/71789/2006]
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-BCM/71789/2006] Funding Source: FCT
The GluA4-containing Ca2+-permeable alpha-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 INK 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. (C) 2010 Elsevier Inc. All rights reserved.
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