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Oxysterol modulates neurotransmission via liver-X receptor/NO synthase-dependent pathway at the mouse neuromuscular junctions.

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.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Mukhutdinova KA,Kasimov MR,Zakyrjanova GF,Gumerova MR,Petrov AM

doi

10.1016/j.neuropharm.2019.03.018

subject

Has Abstract

pub_date

2019-05-15 00:00:00

pages

70-79

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(18)30408-8

journal_volume

150

pub_type

杂志文章

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