Oxysterol modulates neurotransmission via liver-X receptor/NO synthase-dependent pathway at the mouse neuromuscular junctions. (15th May 2019)

• Record Type: Journal Article
• Authors: Mukhutdinova, Kamilla A.; Kasimov, Marat R.; Zakyrjanova, Guzel F.; Gumerova, Milausha R.; Petrov, Alexey M.
• Is Part Of: Neuropharmacology. Volume 150(2019)
• Page Start: 70
• Page End: 79
• Publication Date: 2019-05-15
• Subjects: 24S-hydroxycholesterol -- Oxysterols -- Neuromuscular junction -- Synaptic vesicle exocytosis -- Liver X receptor -- Nitric oxide; eNOS endothelial nitric oxide synthase -- 24S-HCh 24S-hydroxycholesterol -- NMJ neuromuscular junction -- nNOS neuronal nitric oxide synthase -- LXR liver X receptor -- NO nitric oxide; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.03.018
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Elimination of brain cholesterol occurs in the form of 24S-hydroxycholesterol (24S-HCh) that may modulate physiological processes outside the brain. Here, using microelectrode recording of postsynaptic responses (end-plate potentials, EPPs) and fluorescent marker (FM1-43) for endo-exocytosis we studied the effects of prolonged application of 24S-HCh (2.5 h, 0.4 μM) on the neurotransmission in the mice diaphragm. 24S-HCh enhanced the depression of EPP amplitude (indicator of neurotransmitter release) and suppressed the FM1-43 dye unloading from nerve terminals (indicator of exocytosis) during electrical nerve stimulation at 20 Hz, without affecting miniature EPP amplitude and frequency. Comparison of the rates of neurotransmitter and FM1-43 releases suggested an increase in time required for the synaptic vesicle reuse. Additionally, 24S-HCh potentiated an increase in DAF-FM fluorescence (a NO-sensitive marker) in response to 20 Hz stimulation. All effects of 24S-HCh were completely prevented by liver X receptor antagonist. Either inhibitors of NO synthases (TRIM, cavtratin) or protein synthesis blocker counteracted the 24S-HCh-mediated enhancement in DAF-FM fluorescence, while inhibition of NO production with l -NAME or cavtratin and extracellular NO chelation suppressed the effect of 24S-HCh on FM1-43 dye loss during 20 Hz activity. Pretreatment for 5 days with inhibitor of 24S-HCh synthesis (voriconazole) had opposite effects on the FM1-43 unloading and NO synthesis. These data suggest that prolonged exposure to 24S-HCh attenuates recruitment of synaptic vesicle to exocytosis during 20 Hz stimulation acting via liver Х receptor/NO-dependent signaling. Highlights: We studied the role of 24-hydroxycholesterol (24S-HCh) in neurotransmission in diaphragm. Long-term exposure to 24S-HCh depressed neurotransmitter release during 20 Hz stimulation. This was linked with decrease in synaptic vesicle recruitment to exocytosis. The action of 24S-HCh was mediated by increase in NO production mainly by eNOS. Liver X receptor antagonist completely prevented these effects of 24S-HCh.