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
Journal of Biological Chemistry. 2004-12-01; 279(49): 50850-50856
DOI: 10.1074/jbc.M407069200
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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.