Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals

Frédéric Cassé, Isabelle Bardou, Lydia Danglot, Aurélien Briens, Axel Montagne, Jérôme Parcq, Anuradha Alahari, Thierry Galli, Denis Vivien, Fabian Docagne

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Tissue-type plasminogen activator (tPA) regulates physiological processes in the brain, such as learning and memory, and plays a critical role in neuronal survival and neuroinflammation in pathological conditions. Here we demonstrate, by combining mouse in vitro and in vivo data, that tPA is an important element of the cross talk between neurons and astrocytes. The data show that tPA released by neurons is constitutively endocytosed by astrocytes via the low-density lipoprotein-related protein receptor, and is then exocytosed in a regulated manner. The exocytotic recycling of tPA by astrocytes is inhibited in the presence of extracellular glutamate. Kainate receptors of astrocytes act as sensors of extracellular glutamate and, via a signaling pathway involving protein kinase C, modulate the exocytosis of tPA. Further, by thus capturing extracellular tPA, astrocytes serve to reduce NMDA-mediated responses potentiated by tPA. Overall, this work provides the first demonstration that the neuromodulator, tPA, may also be considered as a gliotransmitter.

Original languageEnglish
Pages (from-to)5186-99
Number of pages14
JournalJournal of Neuroscience
Volume32
Issue number15
DOIs
Publication statusPublished - 11 Apr 2012

Keywords / Materials (for Non-textual outputs)

  • Albumins/metabolism
  • Animals
  • Astrocytes/drug effects
  • Cell Death/drug effects
  • Cells, Cultured
  • Clathrin/physiology
  • Dynamins/physiology
  • Endocytosis/drug effects
  • Flow Cytometry
  • Gene Silencing
  • Glutamic Acid/pharmacology
  • Immunohistochemistry
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Mice
  • Neurons/drug effects
  • Plasmids/genetics
  • Protein Kinase C/metabolism
  • RNA/biosynthesis
  • Real-Time Polymerase Chain Reaction
  • Receptors, Kainic Acid/drug effects
  • Receptors, LDL/metabolism
  • Signal Transduction/drug effects
  • Synapsins/metabolism
  • Tissue Plasminogen Activator/metabolism
  • Transfection
  • Tumor Suppressor Proteins/metabolism
  • alpha-Macroglobulins/metabolism

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