24S-hydroxycholesterol suppresses neuromuscular transmission in SOD1(G93A) mice: A possible role of NO and lipid rafts.

Autor: Mukhutdinova KA; Institute of Neuroscience, Kazan State Medial University, Butlerova st. 49, Kazan 420012, Russia., Kasimov MR; Institute of Neuroscience, Kazan State Medial University, Butlerova st. 49, Kazan 420012, Russia., Giniatullin AR; Institute of Neuroscience, Kazan State Medial University, Butlerova st. 49, Kazan 420012, Russia., Zakyrjanova GF; Institute of Neuroscience, Kazan State Medial University, Butlerova st. 49, Kazan 420012, Russia; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center 'Kazan Scientific Center of RAS', P. O. Box 30, Lobachevsky St., 2/31, Kazan 420111, Russia., Petrov AM; Institute of Neuroscience, Kazan State Medial University, Butlerova st. 49, Kazan 420012, Russia; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center 'Kazan Scientific Center of RAS', P. O. Box 30, Lobachevsky St., 2/31, Kazan 420111, Russia. Electronic address: aleksey.petrov@kazangmu.ru.
Jazyk: angličtina
Zdroj: Molecular and cellular neurosciences [Mol Cell Neurosci] 2018 Apr; Vol. 88, pp. 308-318. Date of Electronic Publication: 2018 Mar 14.
DOI: 10.1016/j.mcn.2018.03.006
Abstrakt: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the initial denervation of skeletal muscle and subsequent death of motor neurons. A dying-back pattern of ALS suggests a crucial role for neuromuscular junction dysfunction. In the present study, microelectrode recording of postsynaptic currents and optical detection of synaptic vesicle traffic (FM1-43 dye) and intracellular NO levels (DAF-FM DA) were used to examine the effect of the major brain-derived cholesterol metabolite 24S-hydroxycholesterol (24S-HC, 0.4 μM) on neuromuscular transmission in the diaphragm of transgenic mice carrying a mutant superoxide dismutase 1 (SOD G93A ). We found that 24S-HC suppressed spontaneous neurotransmitter release and neurotransmitter exocytosis during high-frequency stimulation. The latter was accompanied by a decrease in both the rate of synaptic vesicle recycling and activity-dependent enhancement of NO production. Inhibition of NO synthase with L-NAME also attenuated synaptic vesicle exocytosis during high-frequency stimulation and completely abolished the effect of 24S-HC itself. Of note, 24S-HC enhanced the labeling of synaptic membranes with B-subunit of cholera toxin, suggesting an increase in lipid ordering. Lipid raft-disrupting agents (methyl-β-cyclodextrin, sphingomyelinase) prevented the action of 24S-HC on both lipid raft marker labeling and NO synthesis. Together, these experiments indicate that 24S-HC is able to suppress the exocytotic release of neurotransmitter in response to intense activity via a NO/lipid raft-dependent pathway in the neuromuscular junctions of SOD G93A mice.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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