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

Francesc X Soriano, Marc-Andre Martel, Sofia Papadia, Anne Vaslin, Paul Baxter, Colin Rickman, Joan Forder, Michael Tymianski, Rory Duncan, Michelle Aarts, Peter Clarke, David J A Wyllie, Giles E Hardingham

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)10696-710
Number of pages15
JournalJournal of Neuroscience Research
Volume28
Issue number42
DOIs
Publication statusPublished - 2008

Keywords

  • Animals
  • Cell Death
  • Cells, Cultured
  • Excitatory Postsynaptic Potentials
  • Gene Targeting
  • Ligands
  • Male
  • PDZ Domains
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate
  • Signal Transduction

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