Inhibiting pro-death NMDA receptor signaling dependent on the NR2 PDZ ligand may not affect synaptic function or synaptic NMDA receptor signaling to gene expression.
NMDA receptors (NMDARs) mediate ischemic brain damage, in part through interactions of the PDZ ligand of NR2 subunits with the PDZ domain proteins PSD-95 and neuronal nitric oxide synthase located within the NMDAR signaling complex. We have recently shown that this PDZ ligand-dependent pathway promotes neuronal death via p38 activation. A peptide mimetic of the NR2B PDZ ligand (TAT-NR2B9c) reduces p38-mediated death in vitro and p38-dependent ischemic damage in vivo. In the absence of the PDZ ligand-p38 pathway, such as in TAT-NR2B9c-treated neurons, or in NMDAR-expressing non-neuronal cells, NMDAR-dependent excitotoxicity is mediated largely by JNK and requires greater Ca2+ influx. A major reason for blocking pro-death signaling events downstream of the NMDAR as an anti-excitotoxic strategy is that it may spare physiological synaptic function and signaling. We find that neuroprotective doses of TAT-NR2B9c do not alter the frequency of spontaneous synaptic events within networks of cultured cortical neurons nor is mini-EPSC frequency altered. Furthermore, TAT-NR2B9c does not inhibit the capacity of synaptic NMDAR activity to promote neuroprotective changes in gene expression, including the upregulation of PACAP via CREB, and suppression of the pro-oxidative FOXO target gene Txnip. Thus, while the NR2 PDZ ligand does not account for all the excitotoxic effects of excessive NMDAR activity, these findings underline the value of the specific targeting of death pathways downstream of the NMDAR.
Martel
Marc-Andre
MA
Center for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
Soriano
Francesc X
FX
Baxter
Paul
P
Rickman
Colin
C
Duncan
Rory
R
Wyllie
David J A
DJ
Hardingham
Giles E
GE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D052680:Corticotrophs / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D019706:Excitatory Postsynaptic Potentials; D005786:Gene Expression Regulation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008024:Ligands; D051379:Mice; D055369:Miniature Postsynaptic Potentials; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D054731:PDZ Domains; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008024:Ligands; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D052248:Nitric Oxide Synthase Type I; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium