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

J Biol Chem. 2004 Dec 3;279(49):50850-6. doi: 10.1074/jbc.M407069200. Epub 2004 Sep 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / chemistry
  • Amino Acid Sequence
  • Animals
  • Arginine / chemistry*
  • Binding Sites
  • Calcium / chemistry
  • Cell Line
  • Humans
  • Immunoblotting
  • Kinetics
  • Ligands
  • Mass Spectrometry
  • Mice
  • Microscopy, Video
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Neurons / metabolism
  • Point Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, N-Methyl-D-Aspartate / chemistry*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Recombinant Proteins / chemistry
  • Sequence Homology, Amino Acid
  • Signal Transduction*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Temperature
  • Time Factors
  • Tissue Plasminogen Activator / chemistry*
  • Transfection


  • Ligands
  • NR1 NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Arginine
  • Tissue Plasminogen Activator
  • Alanine
  • Calcium