title: Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals.
abstract: 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.
authors.affiliation: Institut National de Santé et de Recherche Médicale, U919, Serine Proteases and Pathophysiology of Neurovascular Unit, Université de Caen, Groupement d'Internet Public Cyceron, 14073 Caen Cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cassé
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bardou
authors.forename: Lydia
authors.initials: L
authors.lastname: Danglot
authors.forename: Aurélien
authors.initials: A
authors.lastname: Briens
authors.forename: Axel
authors.initials: A
authors.lastname: Montagne
authors.forename: Jérôme
authors.initials: J
authors.lastname: Parcq
authors.forename: Anuradha
authors.initials: A
authors.lastname: Alahari
authors.forename: Thierry
authors.initials: T
authors.lastname: Galli
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Fabian
authors.initials: F
authors.lastname: Docagne
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002966:Clathrin / Q000502:physiology; D034281:Dynamins / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D020868:Gene Silencing; D018698:Glutamic Acid / Q000494:pharmacology* / Q000502:physiology*; D007150:Immunohistochemistry; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D016704:Synapsins / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D000418:Albumins; D002966:Clathrin; D034281:Dynamins; D018698:Glutamic Acid; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011493:Protein Kinase C; D012313:RNA; D018092:Kainic Acid Receptors; D011973:Receptors, LDL; D016704:Synapsins; D010959:Tissue Plasminogen Activator; D025521:Tumor Suppressor Proteins; D000511:alpha-Macroglobulins; C486645:Lrp1 protein, mouse