title: Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons.
abstract: The release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons plays a central role in the development of synaptic plasticity, adaptation to metabolic stress and neuronal survival. Our earlier studies indicate that by inducing the recruitment of the cytoskeletal protein βII-spectrin and voltage-gated calcium channels to the active zone, tPA promotes Ca(2+)-dependent translocation of synaptic vesicles (SVs) to the synaptic release site where they release their load of neurotransmitters into the synaptic cleft. Here we used a combination of in vivo and in vitro experiments to investigate whether this effect leads to depletion of SVs in the presynaptic terminal. Our data indicate that tPA promotes SV endocytosis via a mechanism that does not require the conversion of plasminogen into plasmin. Instead, we show that tPA induces calcineurin-mediated dynamin I dephosphorylation, which is followed by dynamin I-induced recruitment of the actin-binding protein profilin II to the presynaptic membrane, and profilin II-induced F-actin formation. We report that this tPA-induced sequence of events leads to the association of newly formed SVs with F-actin clusters in the endocytic zone. In summary, the data presented here indicate that following the exocytotic release of neurotransmitters tPA activates the mechanism whereby SVs are retrieved from the presynaptic membrane and endocytosed to replenish the pool of vesicles available for a new cycle of exocytosis. Together, these results indicate that in murine cerebral cortical neurons tPA plays a central role coupling SVs exocytosis and endocytosis.
authors.affiliation: Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, Veterans Affairs Medical Center, Atlanta, GA, USA. Electronic address: myepes@emory.edu.
authors.forename: M
authors.initials: M
authors.lastname: Yepes
authors.affiliation: Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Torre
authors.affiliation: Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cuellar-Giraldo
authors.affiliation: Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D010959:Tissue Plasminogen Activator
keywords: endocytosis; plasmin; plasminogen; synaptic vesicles; tissue-type plasminogen activator
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