Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

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.

Investigating the Mitoprotective Effects of S1P Receptor Modulators Ex Vivo Using a Novel Semi-Automated Live Imaging Set-Up

“…Others have found that siponimod interacts with the cellular (anti-)oxidant system by, for example, restoring thiol levels and increasing the expression and activity of protective transcription factors [ 31 ]. Moreover, it seems to induce organelle fusion in other models [ 71 ]. We can only speculate why siponimod demonstrated a more pronounced effect on restoring mitochondrial morphology compared to fingolimod in our experiments, despite presumably antagonizing the same S1PR inside the CNS.…”

Phospholipases and Membrane Curvature: What Is Happening at the Surface?

“…The presence of small sphingolipids also influences cellular exocytosis. Sphingosine, a cationic intracellular signaling lipid, greatly increases the release of neurotransmitters in neuronal and neuroendocrine cells, whilst its zwitterionic analogue, sphingosine-1-phosphate (see Table 1 ) inhibited it at low concentrations [ 61 ]. Phospholipase anionic products, such as PA, PIP 2 and other phosphoinositides as well as phosphatidylserine activates the vesicle exocytosis [ 27 ].…”

“…This represents an underestimated mechanism of pharmacological action. Other amphiphilic drugs have been reported to act on the efficiency of vesicle fusion [ 61 ]. However, the pharmacological regulation of membrane curvature properties has seldom been approached and represents a new frontier for the design of new therapies.…”