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dc.contributor.authorClarke, P.en
dc.contributor.authorSoriano, F. X.en
dc.contributor.authorMartel, M. A.en
dc.contributor.authorPapadia, S.en
dc.contributor.authorVaslin, A.en
dc.contributor.authorBaxter, P.en
dc.contributor.authorRickman, C.en
dc.contributor.authorForder, J.en
dc.contributor.authorTymianski, M.en
dc.contributor.authorDuncan, R.en
dc.contributor.authorAarts, M.en
dc.contributor.authorWyllie, David J Aen
dc.contributor.authorHardingham, G. E.en
dc.date.accessioned2009-08-04T12:11:35Z
dc.date.available2009-08-04T12:11:35Z
dc.date.issued2008en
dc.date.issued2008-10-15en
dc.identifier.citationClarke, P., Soriano, F. X., Martel, M. A., Papadia, S.. (2008-10-15) Specific Targeting of Pro-Death NMDA Receptor Signals with Differing Reliance on the NR2B PDZ Ligand, Journal of Neuroscience 28(42) 10696-10710en
dc.identifier.issn0270-6474en
dc.identifier.urihttp://www.jneurosci.org/cgi/reprint/28/42/10696?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=clarke&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCITen
dc.identifier.urihttp://dx.doi.org/10.1523/JNEUROSCI.1207-08.2008en
dc.identifier.urihttp://hdl.handle.net/1842/2977
dc.description.abstractNMDA 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 Ca2+, 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.en
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dc.language.isoen
dc.subjectNMDA receptor; neuronal death; PDZ domains; stroke; calcium; mitochondria; neuroprotection; nitric oxide; protein kinase; signal transductionen
dc.titleSpecific Targeting of Pro-Death NMDA Receptor Signals with Differing Reliance on the NR2B PDZ Liganden
dc.typeArticleen


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