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

Olivier Nicole, Fabian Docagne, Carine Ali, Isabelle Margaill, Peter Carmeliet, Eric T. MacKenzie, Denis Vivien, Alain Buisson
Nat Med. 2001-01-01; 7(1): 59-64
DOI: 10.1038/83358

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1. Nat Med. 2001 Jan;7(1):59-64.

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

Nicole O(1), Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, Vivien D,
Buisson A.

Author information:
(1)Université de CAEN, UMR CNRS 6551, and CEA-Université LRA10V, UPRES EA 2609,
Bd H. Becquerel, Cyeron BP 5229, F-14074 CAEN Cedex, France.

Comment in
Nat Med. 2001 Jan;7(1):17-8.
Nat Med. 2003 Apr;9(4):371-2; author reply 372-3.

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.

DOI: 10.1038/83358
PMID: 11135617 [Indexed for MEDLINE]


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