Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis.
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.
Darios
Frédéric
F
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Wasser
Catherine
C
Shakirzyanova
Anastasia
A
Giniatullin
Artur
A
Goodman
Kerry
K
Munoz-Bravo
Jose L
JL
Raingo
Jesica
J
Jorgacevski
Jernej
J
Kreft
Marko
M
Zorec
Robert
R
Rosa
Juliana M
JM
Gandia
Luis
L
Gutiérrez
Luis M
LM
Binz
Thomas
T
Giniatullin
Rashid
R
Kavalali
Ege T
ET
Davletov
Bazbek
B
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
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