NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity.
Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S(*), 3R(*))-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDAR-dependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.
Baron
A
A
INSERM U, Cyceron, University of Caen Basse-Normandie, Caen, France.
Montagne
A
A
Cassé
F
F
Launay
S
S
Maubert
E
E
Ali
C
C
Vivien
D
D
D000818:Animals; D002478:Cells, Cultured; D003979:Diazonium Compounds / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D003979:Diazonium Compounds; D005343:Fibrinolytic Agents; C464436:NR2D NMDA receptor; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; C056729:4-(2'-pyridyldithio)benzyldiazoacetate; D011189:Potassium Chloride; D010959:Tissue Plasminogen Activator