Is tissue-type plasminogen activator a neuromodulator?

Mol Cell Neurosci. 2004 Apr;25(4):594-601. doi: 10.1016/j.mcn.2003.11.002.


In the last few years, it has been evidenced that serine proteases play key roles in the mammalian brain, both in physiological and pathological conditions. It has been well established that among these serine proteases, the tissue-type plasminogen activator (t-PA) is critically involved in development, plasticity, and pathology of the nervous system. However, its mechanism of action remains to be further investigated. By using pharmacological and immunological approaches, we have evidenced in the present work that t-PA should be considered as a neuromodulator. Indeed, we have observed that: (i). neuronal depolarization induces a release of t-PA; (ii). this release of t-PA is sensitive to exocytosis inhibition and calcium chelation; (iii). released t-PA modulates NMDA receptor signaling and (iv). astrocytes are able to recapture extracellular t-PA through a low-density lipoprotein (LDL) receptor-related protein (LRP)-dependent mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Brain / metabolism*
  • Brain Chemistry / physiology*
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Cell Line
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Chelating Agents / pharmacology
  • Exocytosis / drug effects
  • Exocytosis / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • N-Methylaspartate / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurotransmitter Agents / metabolism*
  • Neurotransmitter Agents / pharmacology
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Tissue Plasminogen Activator / metabolism*
  • Tissue Plasminogen Activator / pharmacology


  • Chelating Agents
  • Glial Fibrillary Acidic Protein
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Microtubule-Associated Proteins
  • Neurotransmitter Agents
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Tissue Plasminogen Activator