Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand.
Détails
Télécharger: 18923045_Postprint.pdf (1821.61 [Ko])
Etat: Public
Version: Author's accepted manuscript
Etat: Public
Version: Author's accepted manuscript
Document(s) secondaire(s)
Télécharger: 10696.full.pdf (876.83 [Ko])
Etat: Public
Version: Final published version
Etat: Public
Version: Final published version
ID Serval
serval:BIB_FD43A45CC8B7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand.
Périodique
Journal of Neuroscience
ISSN
1529-2401 (electronic)
0270-6474 (linking)
0270-6474 (linking)
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
28
Numéro
42
Pages
10696-10710
Langue
anglais
Résumé
NMDA receptors (NMDARs) mediate ischemic brain damage, for which interactions between the C termini of NR2 subunits and PDZ domain proteins within the NMDAR signaling complex (NSC) are emerging therapeutic targets. However, expression of NMDARs in a non-neuronal context, lacking many NSC components, can still induce cell death. Moreover, it is unclear whether targeting the NSC will impair NMDAR-dependent prosurvival and plasticity signaling. We show that the NMDAR can promote death signaling independently of the NR2 PDZ ligand, when expressed in non-neuronal cells lacking PSD-95 and neuronal nitric oxide synthase (nNOS), key PDZ proteins that mediate neuronal NMDAR excitotoxicity. However, in a non-neuronal context, the NMDAR promotes cell death solely via c-Jun N-terminal protein kinase (JNK), whereas NMDAR-dependent cortical neuronal death is promoted by both JNK and p38. NMDAR-dependent pro-death signaling via p38 relies on neuronal context, although death signaling by JNK, triggered by mitochondrial reactive oxygen species production, does not. NMDAR-dependent p38 activation in neurons is triggered by submembranous Ca(2+), and is disrupted by NOS inhibitors and also a peptide mimicking the NR2B PDZ ligand (TAT-NR2B9c). TAT-NR2B9c reduced excitotoxic neuronal death and p38-mediated ischemic damage, without impairing an NMDAR-dependent plasticity model or prosurvival signaling to CREB or Akt. TAT-NR2B9c did not inhibit JNK activation, and synergized with JNK inhibitors to ameliorate severe excitotoxic neuronal loss in vitro and ischemic cortical damage in vivo. Thus, NMDAR-activated signals comprise pro-death pathways with differing requirements for PDZ protein interactions. These signals are amenable to selective inhibition, while sparing synaptic plasticity and prosurvival signaling.
Mots-clé
Animals, Cell Death/physiology, Cells, Cultured, Excitatory Postsynaptic Potentials/physiology, Gene Targeting/methods, Ligands, Male, PDZ Domains/physiology, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate/genetics, Receptors, N-Methyl-D-Aspartate/metabolism, Signal Transduction/physiology
Pubmed
Web of science
Open Access
Oui
Création de la notice
30/01/2009 11:13
Dernière modification de la notice
20/08/2019 17:28