title: TI-VAMP/VAMP7 is the SNARE of secretory lysosomes contributing to ATP secretion from astrocytes.
abstract: BACKGROUND
  ATP is the main transmitter stored and released from astrocytes under physiological and pathological conditions. Morphological and functional evidence suggest that besides secretory granules, secretory lysosomes release ATP. However, the molecular mechanisms involved in astrocytic lysosome fusion remain still unknown.
  
  
  RESULTS
  In the present study, we identify tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP, also called VAMP7) as the vesicular SNARE which mediates secretory lysosome exocytosis, contributing to release of both ATP and cathepsin B from glial cells. We also demonstrate that fusion of secretory lysosomes is triggered by slow and locally restricted calcium elevations, distinct from calcium spikes which induce the fusion of glutamate-containing clear vesicles. Downregulation of TI-VAMP/VAMP7 expression inhibited the fusion of ATP-storing vesicles and ATP-mediated calcium wave propagation. TI-VAMP/VAMP7 downregulation also significantly reduced secretion of cathepsin B from glioma.
  
  
  CONCLUSIONS
  Given that sustained ATP release from glia upon injury greatly contributes to secondary brain damage and cathepsin B plays a critical role in glioma dissemination, TI-VAMP silencing can represent a novel strategy to control lysosome fusion in pathological conditions.
authors.affiliation: Department of Medical Pharmacology and CNR Institute of Neuroscience, Università di Milano, 20129 Milan, Italy. c.verderio@in.cnr.it
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cagnoli
authors.forename: Matteo
authors.initials: M
authors.lastname: Bergami
authors.forename: Maura
authors.initials: M
authors.lastname: Francolini
authors.forename: Ursula
authors.initials: U
authors.lastname: Schenk
authors.forename: Alessio
authors.initials: A
authors.lastname: Colombo
authors.forename: Loredana
authors.initials: L
authors.lastname: Riganti
authors.forename: Carolina
authors.initials: C
authors.lastname: Frassoni
authors.forename: Emanuela
authors.initials: E
authors.lastname: Zuccaro
authors.forename: Lydia
authors.initials: L
authors.lastname: Danglot
authors.forename: Claire
authors.initials: C
authors.lastname: Wilhelm
authors.forename: Thierry
authors.initials: T
authors.lastname: Galli
authors.forename: Marco
authors.initials: M
authors.lastname: Canossa
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian; D005089:Exocytosis; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008561:Membrane Fusion; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D061251:Primary Cell Culture; D011485:Protein Binding; D050683:R-SNARE Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D014162:Transfection
chemical_list: D050683:R-SNARE Proteins; D034741:RNA, Small Interfering; C121241:VAMP7 protein, human; C496926:Vamp7 protein, rat; D000255:Adenosine Triphosphate; D002401:Cathepsin B; D002118:Calcium