title: The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling.
abstract: 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.
authors.affiliation: Université de CAEN, UMR CNRS 6551, and CEA-Université LRA10V, UPRES EA 2609, Bd H. Becquerel, Cyeron BP 5229, F-14074 CAEN Cedex, France.
authors.forename: O
authors.initials: O
authors.lastname: Nicole
authors.forename: F
authors.initials: F
authors.lastname: Docagne
authors.forename: C
authors.initials: C
authors.lastname: Ali
authors.forename: I
authors.initials: I
authors.lastname: Margaill
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
authors.forename: E T
authors.initials: ET
authors.lastname: MacKenzie
authors.forename: D
authors.initials: D
authors.lastname: Vivien
authors.forename: A
authors.initials: A
authors.lastname: Buisson
mesh_terms: 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*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D010959:Tissue Plasminogen Activator; D002118:Calcium