title: Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis.
abstract: Synaptic vesicles loaded with neurotransmitters fuse with the plasma membrane to release their content into the extracellular space, thereby allowing neuronal communication. The membrane fusion process is mediated by a conserved set of SNARE proteins: vesicular synaptobrevin and plasma membrane syntaxin and SNAP-25. Recent data suggest that the fusion process may be subject to regulation by local lipid metabolism. Here, we have performed a screen of lipid compounds to identify positive regulators of vesicular synaptobrevin. We show that sphingosine, a releasable backbone of sphingolipids, activates synaptobrevin in synaptic vesicles to form the SNARE complex implicated in membrane fusion. Consistent with the role of synaptobrevin in vesicle fusion, sphingosine upregulated exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and hippocampal neurons, but not in neurons obtained from synaptobrevin-2 knockout mice. Further mechanistic insights suggest that sphingosine acts on the synaptobrevin/phospholipid interface, defining a novel function for this important lipid regulator.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Darios
authors.forename: Catherine
authors.initials: C
authors.lastname: Wasser
authors.forename: Anastasia
authors.initials: A
authors.lastname: Shakirzyanova
authors.forename: Artur
authors.initials: A
authors.lastname: Giniatullin
authors.forename: Kerry
authors.initials: K
authors.lastname: Goodman
authors.forename: Jose L
authors.initials: JL
authors.lastname: Munoz-Bravo
authors.forename: Jesica
authors.initials: J
authors.lastname: Raingo
authors.forename: Jernej
authors.initials: J
authors.lastname: Jorgacevski
authors.forename: Marko
authors.initials: M
authors.lastname: Kreft
authors.forename: Robert
authors.initials: R
authors.lastname: Zorec
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Rosa
authors.forename: Luis
authors.initials: L
authors.lastname: Gandia
authors.forename: Luis M
authors.initials: LM
authors.lastname: Gutiérrez
authors.forename: Thomas
authors.initials: T
authors.lastname: Binz
authors.forename: Rashid
authors.initials: R
authors.lastname: Giniatullin
authors.forename: Ege T
authors.initials: ET
authors.lastname: Kavalali
authors.forename: Bazbek
authors.initials: B
authors.lastname: Davletov
mesh_terms: D000818:Animals; D001921:Brain / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000172:deficiency
chemical_list: D004791:Enzyme Inhibitors; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D050600:SNARE Proteins; D050825:Synaptosomal-Associated Protein 25; D050988:Vesicle-Associated Membrane Protein 2; D013110:Sphingosine; C005682:safingol; D002118:Calcium