MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
Hôpital Pitié Salpêtrière, ICM, 75013, Paris, France.
Sci Rep. 2017 Jul 20;7(1):5958. doi: 10.1038/s41598-017-05948-z.
Neurotransmission and secretion of hormones involve a sequence of protein/lipid interactions with lipid turnover impacting on vesicle trafficking and ultimately fusion of secretory vesicles with the plasma membrane. We previously demonstrated that sphingosine, a sphingolipid metabolite, promotes formation of the SNARE complex required for membrane fusion and also increases the rate of exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and in hippocampal neurons. Recently a fungi-derived sphingosine homologue, FTY720, has been approved for treatment of multiple sclerosis. In its non-phosphorylated form FTY720 accumulates in the central nervous system, reaching high levels which could affect neuronal function. Considering close structural similarity of sphingosine and FTY720 we investigated whether FTY720 has an effect on regulated exocytosis. Our data demonstrate that FTY720 can activate vesicular synaptobrevin for SNARE complex formation and enhance exocytosis in neuroendocrine cells and neurons.
神经递质的传递和激素分泌涉及一系列蛋白质/脂质相互作用，脂质周转会影响囊泡运输，最终影响分泌囊泡与质膜融合。我们之前的研究表明，神经酰胺是一种鞘脂类代谢物，可促进膜融合所需 SNARE 复合物的形成，同时增加分离神经末梢、神经肌肉接头、神经内分泌细胞和海马神经元中胞吐的速率。最近，一种真菌衍生的神经酰胺类似物，FTY720，已被批准用于多发性硬化症的治疗。在非磷酸化形式下，FTY720 在中枢神经系统中积累，达到可能影响神经元功能的高水平。鉴于神经酰胺和 FTY720 的结构非常相似，我们研究了 FTY720 是否对受调控的胞吐作用有影响。我们的数据表明，FTY720 可以激活囊泡相关蛋白 SNAP25 形成 SNARE 复合物，并增强神经内分泌细胞和神经元中的胞吐作用。
