Sphingosine Facilitates SNARE Complex Assembly and Activates Synaptic Vesicle Exocytosis

• Published in: Neuron (Cambridge, Mass.) Vol. 62; no. 5; pp. 683 - 694
• Main Authors: Darios, Frédéric, Wasser, Catherine, Shakirzyanova, Anastasia, Giniatullin, Artur, Goodman, Kerry, Munoz-Bravo, Jose L., Raingo, Jesica, Jorgačevski, Jernej, Kreft, Marko, Zorec, Robert, Rosa, Juliana M., Gandia, Luis, Gutiérrez, Luis M., Binz, Thomas, Giniatullin, Rashid, Kavalali, Ege T., Davletov, Bazbek
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-06-2009; Elsevier Limited; Cell Press
• Subjects: Acids; Animals; Brain - ultrastructure; Calcium - metabolism; Cattle; CELLBIO; Cells, Cultured; Chromaffin Cells; Dopamine; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Exocytosis - physiology; Experiments; Glycerol; Grants; Hippocampus - cytology; In Vitro Techniques; Lipids; Membrane Potentials - drug effects; Membrane Potentials - physiology; Membranes; Mice; Mice, Knockout; MOLNEURO; Neuromuscular Junction - drug effects; Neuromuscular Junction - physiology; Neurons - drug effects; Neurons - physiology; Patch-Clamp Techniques; Plasma; Qa-SNARE Proteins - genetics; Qa-SNARE Proteins - metabolism; R-SNARE Proteins - genetics; R-SNARE Proteins - metabolism; Rats; Regulation; SIGNALING; SNARE Proteins - metabolism; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine - pharmacology; Studies; Synaptic Vesicles - drug effects; Synaptic Vesicles - physiology; Synaptosomal-Associated Protein 25 - metabolism; Vesicle-Associated Membrane Protein 2 - deficiency; CELLBIO; MOLNEURO; SIGNALING
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2009.04.024

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.