Abstract
The fusion of membranes is a central part of the physiological processes involving the intracellular transport and maturation of vesicles and the final release of their contents, such as neurotransmitters and hormones, by exocytosis. Traditionally, in this process, proteins, such SNAREs have been considered the essential components of the fusion molecular machinery, while lipids have been seen as merely structural elements. Nevertheless, sphingosine, an intracellular signalling lipid, greatly increases the release of neurotransmitters in neuronal and neuroendocrine cells, affecting the exocytotic fusion mode through the direct interaction with SNAREs. Moreover, recent studies suggest that FTY-720 (Fingolimod), a sphingosine structural analogue used in the treatment of multiple sclerosis, simulates sphingosine in the promotion of exocytosis. Furthermore, this drug also induces the intracellular fusion of organelles such as dense vesicles and mitochondria causing cell death in neuroendocrine cells. Therefore, the effect of sphingosine and synthetic derivatives on the heterologous and homologous fusion of organelles can be considered as a new mechanism of action of sphingolipids influencing important physiological processes, which could underlie therapeutic uses of sphingosine derived lipids in the treatment of neurodegenerative disorders and cancers of neuronal origin such neuroblastoma.
Highlights
In collaboration with Dr Alvarez de Toledo at the University of Seville we performed experiments using the whole cell and on-cell capacitance techniques to resolve the size of the vesicles fused and we found that sphingomyelinase treatment of rat chromaffin cells resulted in a clear increase in the frequency of fusions of both small and large vesicles without affecting the size of the vesicles measured by electron microscopy [39], in agreement with the results obtained in lactotrophops [53]
We reported that FTY-720 has a complex effect on secretion from neuroendocrine chromaffin cells because, in addition to modifying the amount of quantal release and the frequency of vesicle fusion in cells stimulated by depolarizations, we observed that the recruitment of vesicles in response to multiple pulses decreases, indicating that late phases of vesicle transport are altered [64]
It is possible that both sphingosine and FTY-720, in addition to altering the vesicle fusion properties in neuroendocrine and neuronal systems through the alteration of SNARE function, these small lipids could alter the transport of vesicles through F-actin cytoskeleton, impairing vesicle access to secretory sites and that this could be related with the alteration of calcium dynamics by sphingolipids [55]
Summary
The fusion of vesicles with other lipid bilayers is essential for intracellular trafficking and release of neurotransmitters and hormones [1,2,3,4]. Lipids can be incorporated into secretory proteins such as SNAP-25 via post-translational modification consisting in the acylation of cysteine residues by palmitate, a saturated 16-carbon fatty acid and in that way affect the location and the function of this protein [22]. It seems that the palmitoylation of 4 residues of this SNARE, increase the clustering of SNAP-25 in cholesterol and sphingomyelin rich lipid rafts, that could enhance the formation of secretory active sites thereby acting as a cohesive factor [23,24]. As can be deduced from the multiple roles played by lipids mentioned above, their function in exocytosis is far more complex than that deduced from being the basic structural elements forming membranes, and this is further supported by recent data on the direct modulation of the secretory machinery by signalling lipids
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