Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor.
Cells preferentially expressing GluR4-containing alpha-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.
Santos
A E
AE
Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.
Duarte
C B
CB
Iizuka
M
M
Barsoumian
E L
EL
Ham
J
J
Lopes
M C
MC
Carvalho
A P
AP
Carvalho
A L
AL
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D021122:Protein Subunits; D018091:Receptors, AMPA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D001581:Benzothiadiazines; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D021122:Protein Subunits; D018091:Receptors, AMPA; D018808:Transcription Factor AP-1; C104724:glutamate receptor ionotropic, AMPA 4; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D004247:DNA; C004639:cyclothiazide; D002118:Calcium