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J. Biol. Chem., Vol. 279, Issue 49, 50850-50856, December 3, 2004

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Arginine 260 of the Amino-terminal Domain of NR1 Subunit Is Critical for Tissue-type Plasminogen Activator-mediated Enhancement of N-Methyl-D-aspartate Receptor Signaling^*

Mónica Fernández-Monreal¶, José P. López-Atalaya||, Karim Benchenane**, Mathias Cacquevel||, Fabienne Dulin, Jean-Pierre Le Caer, Jean Rossier, Anne-Charlotte Jarrige, Eric T. MacKenzie, Nathalie Colloc'h, Carine Ali, and Denis Vivien¶¶

From the CNRS UMR 6185, University of Caen, Centre Cyceron, Bd. Henri Becquerel, BP 5229, 14074, Caen cedex, France, Ecole Polytechnique CNRS UMR 7651, 91128 Palaiseau Cedex, France, and ESPCI, CNRS UMR 7637, 75231 Paris cedex 5, France

Tissue-type plasminogen activator (tPA) has been involved in both physiological and pathological glutamatergic-dependent processes, such as synaptic plasticity, seizure, trauma, and stroke. In a previous study, we have shown that the proteolytic activity of tPA enhances the N-methyl-D-aspartate (NMDA) receptor-mediated signaling in neurons (Nicole, O., Docagne, F., Ali, C., Margaill, I., Carmeliet, P., MacKenzie, E. T., Vivien, D., and Buisson, A. (2001) Nat. Med. 7, 59–64). Here, we show that tPA forms a direct complex with the amino-terminal domain (ATD) of the NR1 subunit of the NMDA receptor and cleaves this subunit at the arginine 260. Furthermore, point mutation analyses show that arginine 260 is necessary for both tPA-induced cleavage of the ATD of NR1 and tPA-induced potentiation of NMDA receptor signaling. Thus, tPA is the first binding protein described so far to interact with the ATD of NR1 and to modulate the NMDA receptor function.

Received for publication, June 24, 2004 , and in revised form, September 20, 2004.

^* This work was supported by grants from the CNRS, University of Caen and European Council (FEDER). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^¶ Supported by the Fondation pour la Recherche Medicale.

^|| Supported by the Regional Council of Lower Normandy.

^** Supported by the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche.

^¶¶ To whom correspondence should be addressed. Tel.: 33-231-56-6039; Fax: 33-231-56-61-99; E-mail: d.vivien{at}neuro.unicaen.fr.

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