The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling.
Tissue-plasminogen activator (t-PA) is now available for the treatment of thrombo-embolic stroke but adverse effects have been reported in some patients, particularly hemorrhaging. In contrast, the results of animal studies have indicated that t-PA could increase neuronal damage after focal cerebral ischemia. Here we report for the first time that t-PA potentiates signaling mediated by glutamatergic receptors by modifying the properties of the N-methyl-D-aspartate (NMDA) receptor. When depolarized, cortical neurons release bio-active t-PA that interacts with and cleaves the NR1 subunit of the NMDA receptor. Moreover, the treatment with recombinant t-PA leads to a 37% increase in NMDA-stimulated fura-2 fluorescence, which may reflect an increased NMDA-receptor function. These results were confirmed in vivo by the intrastriatal injection of recombinant-PA, which potentiated the excitotoxic lesions induced by NMDA. These data provide insight into the regulation of NMDA-receptor-mediated signaling and could initiate therapeutic strategies to improve the efficacy of t-PA treatment in man.
Nicole
O
O
Université de CAEN, UMR CNRS 6551, and CEA-Université LRA10V, UPRES EA 2609, Bd H. Becquerel, Cyeron BP 5229, F-14074 CAEN Cedex, France.
Docagne
F
F
Ali
C
C
Margaill
I
I
Carmeliet
P
P
MacKenzie
E T
ET
Vivien
D
D
Buisson
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D006868:Hydrolysis; D017136:Ion Transport; D008564:Membrane Potentials; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate; D010959:Tissue Plasminogen Activator; D002118:Calcium