The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling

Nat Med. 2001 Jan;7(1):59-64. doi: 10.1038/83358.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Death
  • Hydrolysis
  • Ion Transport
  • Membrane Potentials
  • Neurons / metabolism
  • Neurons / physiology
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction*
  • Tissue Plasminogen Activator / metabolism*


  • Receptors, N-Methyl-D-Aspartate
  • Tissue Plasminogen Activator
  • Calcium