Excitotoxicity through Ca2+-permeable AMPA receptors requires Ca2+-dependent JNK activation.
The GluA4-containing Ca(2+)-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 Ca(2+) 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.
Vieira
M
M
Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Fernandes
J
J
Burgeiro
A
A
Thomas
G M
GM
Huganir
R L
RL
Duarte
C B
CB
Carvalho
A L
AL
Santos
A E
AE
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007608:Kainic Acid / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D018690:Excitatory Amino Acid Agonists; C490666:MAPK8IP1 protein, human; D018091:Receptors, AMPA; D048670:MAP Kinase Kinase 4; D007608:Kainic Acid; D002118:Calcium