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|Title: ||Specific Targeting of Pro-Death NMDA Receptor Signals with Differing Reliance on the NR2B PDZ Ligand|
|Authors: ||Clarke, P.|
Soriano, F. X.
Martel, M. A.
Wyllie, David J A
Hardingham, G. E.
|Issue Date: ||2008|
|Citation: ||Clarke, 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) 10696-10710|
|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 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.|
|Keywords: ||NMDA receptor; neuronal death; PDZ domains; stroke; calcium; mitochondria; neuroprotection; nitric oxide; protein kinase; signal transduction|
|Appears in Collections:||Royal (Dick) School of Veterinary Studies publications|
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