Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function

J Neurochem. 2008 Nov;107(4):1091-101. doi: 10.1111/j.1471-4159.2008.05687.x. Epub 2008 Sep 15.


Glutamate is the main excitatory neurotransmitter of the CNS. Tissue-type plasminogen activator (tPA) is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate-binding NMDA receptor (NMDAR). It has been hypothesized that tPA can directly cleave the NR1 subunit of the NMDAR and thereby potentiate NMDA-induced calcium influx. In contrast, here we show that this increase in NMDAR signaling requires tPA to be proteolytically active, but does not involve cleavage of the NR1 subunit or plasminogen. Rather, we demonstrate that enhancement of NMDAR function by tPA is mediated by a member of the low-density lipoprotein receptor (LDLR) family. Hence, this study proposes a novel functional relationship between tPA, the NMDAR, a LDLR and an unknown substrate which we suspect to be a serpin. Interestingly, whilst tPA alone failed to cleave NR1, cell-surface NMDARs did serve as an efficient and discrete proteolytic target for plasmin. Hence, plasmin and tPA can affect the NMDAR via distinct avenues. Altogether, we find that plasmin directly proteolyses the NMDAR whilst tPA functions as an indirect modulator of NMDA-induced events via LDLR engagement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Animals, Newborn
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Drug Interactions
  • Fibrinolysin / pharmacology
  • Glutamic Acid / pharmacology
  • Glycine / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Potentials / radiation effects
  • Mice
  • Mice, Inbred C57BL
  • N-Methylaspartate / pharmacology
  • Neurons / drug effects
  • Oocytes
  • Patch-Clamp Techniques
  • Protease Nexins
  • Rats
  • Receptors, Cell Surface / metabolism
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Thrombin / pharmacology
  • Tissue Plasminogen Activator / pharmacology*
  • Xenopus laevis
  • rap GTP-Binding Proteins / pharmacology


  • Amyloid beta-Protein Precursor
  • Protease Nexins
  • Receptors, Cell Surface
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • N-Methylaspartate
  • Thrombin
  • Tissue Plasminogen Activator
  • Fibrinolysin
  • rap GTP-Binding Proteins
  • Calcium
  • Glycine