Alterations of calcium homoeostasis in cultured rat astrocytes evoked by bioactive sphingolipids

Stenovec, Matjaž; Trkov, Saša; Kreft, Marko; Zorec, Robert

doi:10.1111/apha.12314

Cited by 23 publications

(29 citation statements)

References 68 publications

(70 reference statements)

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“…The structural analogy of FTY720 with sphingosine could underlie the observed recruitment of synaptobrevin for SNARE complex assembly thereby enhancing regulated exocytosis. Although our data do not rule out further effects of FTY720 which could contribute to enhanced exocytosis 9 , we would like to propose that this sphingomimetic drug can also uplift the cytoplasmic part of synaptobrevin thereby activating SNARE assembly for vesicle exocytosis. We do not necessarily envisage that FTY720 directly binds to synaptobrevin – it is possible that after incorporation into the synaptic vesicle membrane the positively charged amphiphilic FTY720 changes the interface between synaptobrevin and the negatively charged surface of the vesicular membrane.…”

Section: Discussionmentioning

confidence: 57%

“…The need for well-defined therapeutic targets for FTY720 and related drugs has been highlighted 8 . Recent studies demonstrated the role of FTY720 on specific functions of astrocytes such as cytoskeleton 10, 45 , vesicle traffic and calcium homeostasis 9, 46 . In PC12 neuronal model cells, micromolar concentrations of FTY720 activated intracellular protein phosphatase 2 A (PP2A), an important modulator of neuronal function 47 .…”

Section: Discussionmentioning

confidence: 99%

“…Emerging data from experimental animal models suggest that fingolimod may have additional therapeutic applications. Recently, significant effects of FTY720 have been demonstrated in modulation of astrocyte function, neural excitability and anti-cancer effects 9, 10 . FTY720 readily crosses the blood brain barrier and accumulates in the CNS 11, 12 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion

Darios

Jorgačevski

Flašker

et al. 2017

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion

Darios

Jorgačevski

Flašker

et al. 2017

Sci Rep

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“…It is known that ATP stimulation transiently attenuates endo/lysosomal vesicle mobility in astrocytes . Thus we investigated whether nestin deficiency interferes with the stimulation‐dependent attenuation of vesicle mobility.…”

Section: Resultsmentioning

confidence: 99%

Nestin affects fusion pore dynamics in mouse astrocytes

et al. 2019

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Aim Astrocytes play a homeostatic role in the central nervous system and influence numerous aspects of neurophysiology via intracellular trafficking of vesicles. Intermediate filaments (IFs), also known as nanofilaments, regulate a number of cellular processes including organelle trafficking and adult hippocampal neurogenesis. We have recently demonstrated that the IF protein nestin, a marker of neural stem cells and immature and reactive astrocytes, is also expressed in some astrocytes in the unchallenged hippocampus and regulates neurogenesis through Notch signalling from astrocytes to neural stem cells, possibly via altered trafficking of vesicles containing the Notch ligand Jagged‐1. Methods We thus investigated whether nestin affects vesicle dynamics in astrocytes by examining single vesicle interactions with the plasmalemma and vesicle trafficking with high‐resolution cell‐attached membrane capacitance measurements and confocal microscopy. We used cell cultures of astrocytes from nestin‐deficient (Nes−/−) and wild‐type (wt) mice, and fluorescent dextran and Fluo‐2 to examine vesicle mobility and intracellular Ca2+ concentration respectively. Results Nes−/− astrocytes exhibited altered sizes of vesicles undergoing full fission and transient fusion, altered vesicle fusion pore geometry and kinetics, decreased spontaneous vesicle mobility and altered ATP‐evoked mobility. Purinergic stimulation evoked Ca2+ signalling that was slightly attenuated in Nes−/− astrocytes, which exhibited more oscillatory Ca2+ responses than wt astrocytes. Conclusion These results demonstrate at the single vesicle level that nestin regulates vesicle interactions with the plasmalemma and vesicle trafficking, indicating its potential role in astrocyte vesicle‐based communication.

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“…In astrocytes, sphingosine analogue FTY720 (fingolimod), currently used for treatment of multiple sclerosis, strongly affects vesicle mobility and the release of peptides from a single vesicle [84]. This is associated with a change in Ca 2+ homeostasis in astrocytes [85]. …”

Section: Vesicle Traffic Surface Signalling Landscape Of Astrocytmentioning

confidence: 99%

Astrocytic Pathological Calcium Homeostasis and Impaired Vesicle Trafficking in Neurodegeneration

Vardjan

Verkhratsky

Zorec

2017

IJMS

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Although the central nervous system (CNS) consists of highly heterogeneous populations of neurones and glial cells, clustered into diverse anatomical regions with specific functions, there are some conditions, including alertness, awareness and attention that require simultaneous, coordinated and spatially homogeneous activity within a large area of the brain. During such events, the brain, representing only about two percent of body mass, but consuming one fifth of body glucose at rest, needs additional energy to be produced. How simultaneous energy procurement in a relatively extended area of the brain takes place is poorly understood. This mechanism is likely to be impaired in neurodegeneration, for example in Alzheimer’s disease, the hallmark of which is brain hypometabolism. Astrocytes, the main neural cell type producing and storing glycogen, a form of energy in the brain, also hold the key to metabolic and homeostatic support in the central nervous system and are impaired in neurodegeneration, contributing to the slow decline of excitation-energy coupling in the brain. Many mechanisms are affected, including cell-to-cell signalling. An important question is how changes in cellular signalling, a process taking place in a rather short time domain, contribute to the neurodegeneration that develops over decades. In this review we focus initially on the slow dynamics of Alzheimer’s disease, and on the activity of locus coeruleus, a brainstem nucleus involved in arousal. Subsequently, we overview much faster processes of vesicle traffic and cytosolic calcium dynamics, both of which shape the signalling landscape of astrocyte-neurone communication in health and neurodegeneration.

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Alterations of calcium homoeostasis in cultured rat astrocytes evoked by bioactive sphingolipids

Abstract: Exogenously added cell-permeable sphingosine-like lipids exert complex, Ca(2+)-dependent effects on astrocytes and likely alter their homeostatic function in vivo.

Cited by 23 publications

References 68 publications

Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion

Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion

Nestin affects fusion pore dynamics in mouse astrocytes

Astrocytic Pathological Calcium Homeostasis and Impaired Vesicle Trafficking in Neurodegeneration

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