25-Hydroxycholesterol modulates synaptic vesicle endocytosis at the mouse neuromuscular junction

Kuznetsova, E.A.; Zakirjanova, G.F.; Tsentsevitsky, A.N.; Petrov, A.M.

Авторы: Kuznetsova Eva A., Zakirjanova Guzalia F., Tsentsevitsky Andrei N., Petrov Alexey M.
Журнал: Pflugers Archiv European Journal of Physiology
Том: 477
Номер: 3
Год издания: 2025
Издательство: Springer Verlag
Местоположение издательства: Germany
Первая страница: 421
Последняя страница: 439
DOI: 10.1007/s00424-024-03058-0
Аннотация: Many synaptic vesicles undergo exocytosis in motor nerve terminals during neuromuscular communication. Endocytosis then recovers the synaptic vesicle pool and presynaptic membrane area. The kinetics of endocytosis may shape neuromuscular transmission, determining its long-term reliability. Here, using fluorescent dyes, the time course of endocytosis induced by intense activity of the phrenic nerve was studied at the mouse diaphragm neuromuscular junction. It was found that a significant portion of endocytic events occurs after the end of tetanic stimulation. Pitstop 2, clathrin inhibitor, and more profoundly dynole 34-2, dynamin antagonist, suppressed endocytic FM1-43 dye uptake both during and after tetanus. Furthermore, synaptic vesicles formed in the presence of the endocytic blockers released FM-dye during subsequent evoked exocytosis at a lower rate. 25-Hydroxycholesterol (25HC) is an oxysterol, ubiquitously synthetized from excessive cholesterol. In addition, its production greatly increases by activated macrophages. 25HC accelerated FM-dye endocytosis and its sequential evoked exocytosis, and dynole (but not pitstop) prevented 25HC-mediated enhancement of endocytic FM-dye uptake. The positive effects of 25HC were interfered with chelation of cytosolic Ca2+ with a slow Ca2+ buffer EGTA-AM, Ca2+ antagonist TMB8, and sphingomyelin-hydrolyzing enzyme. In contrast to amphiphilic FM1-43 dye capture, 25HC reduced uptake of hydrophilic high molecular weight markers (labeled dextrans and toxin), which utilize bulk endocytosis to enter into nerve terminals. Thus, synaptic vesicle endocytosis had a relatively slow kinetics following the tetanic activity and can be accelerated by 25HC. The positive effect of 25HC on endocytosis engages a dynamin-dependent pathway, interconnected with cytoplasmic Ca2+ and sphingomyelin integrity.
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25-Hydroxycholesterol modulates synaptic vesicle endocytosis at the mouse neuromuscular junctionстатья Исследовательская статья

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