Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand.

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Version: Author's accepted manuscript
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Version: Final published version
Serval ID
serval:BIB_FD43A45CC8B7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand.
Journal
Journal of Neuroscience
Author(s)
Soriano F.X., Martel M.A., Papadia S., Vaslin A., Baxter P., Rickman C., Forder J., Tymianski M., Duncan R., Aarts M., Clarke P.G.H., Wyllie D.J., Hardingham G.E.
ISSN
1529-2401 (electronic)
0270-6474 (linking)
Publication state
Published
Issued date
2008
Peer-reviewed
Oui
Volume
28
Number
42
Pages
10696-10710
Language
english
Abstract
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.
Keywords
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
Yes
Create date
30/01/2009 10:13
Last modification date
20/08/2019 16:28
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