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

M. Vieira, J. Fernandes, A. Burgeiro, G. M. Thomas, R. L. Huganir, C. B. Duarte, A. L. Carvalho, A. E. Santos

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


The GluA4-containing Ca2+-permeable β-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.

Original languageEnglish (US)
Pages (from-to)645-655
Number of pages11
JournalNeurobiology of Disease
Issue number3
StatePublished - Dec 2010


  • AMPA receptors
  • AP-1 transcription factor
  • Calcium channels
  • Cell death
  • Excitotoxicity
  • JNK
  • Transient global ischemia

ASJC Scopus subject areas

  • Neurology


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