20.500.12556/RUL-138888 Vesicle cholesterol controls exocytotic fusion pore In some lysosomal storage diseases (LSD) cholesterol accumulates in vesicles. Whether increased vesicle cholesterol affects vesicle fusion with the plasmalemma, where the fusion pore, a channel between the vesicle lumen and the extracellular space, is formed, is unknown. Super-resolution microscopy revealed that after stimulation of exocytosis, pituitary lactotroph vesicles discharge cholesterol which transfers to the plasmalemma. Cholesterol depletion in lactotrophs and astrocytes, both exhibiting Ca$^{2+}$-dependent exocytosis regulated by distinct Ca$^{2+}$ sources, evokes vesicle secretion. Although this treatment enhanced cytosolic levels of Ca$^{2+}$ in lactotrophs but decreased it in astrocytes, this indicates that cholesterol may well directly define the fusion pore. In an attempt to explain this mechanism, a new model of cholesterol-dependent fusion pore regulation is proposed. High-resolution membrane capacitance measurements, used to monitor fusion pore conductance, a parameter related to fusion pore diameter, confirm that at resting conditions reducing cholesterol increases, while enrichment with cholesterol decreases the conductance of the fusion pore. In resting fibroblasts, lacking the Npc1 protein, a cellular model of LSD in which cholesterol accumulates in vesicles, the fusion pore conductance is smaller than in controls, showing that vesicle cholesterol controls fusion pore and is relevant for pathophysiology of LSD. cholesterol exocytosis fusion pore conductance constriction force fusion pore widening and constriction lysosomal storage disease holesterol eksocitoza prevodnost fuzijskih por true false true Angleški jezik Slovenski jezik Članek v reviji 2022-08-24 13:01:53 2022-08-24 13:01:59 2023-05-05 13:04:08 0000-00-00 00:00:00 2022 0 0 17 str. Vol. 101, art. 102503 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-092 1532-1991 10.1016/j.ceca.2021.102503 87034627 1-s2.0-S0143416021001573-main.pdf 1-s2.0-S0143416021001573-main.pdf 1 C7C4CA7C2FF0149F5636E1FA99C80A60 945c29cf4ab3a96efec3f2ba20f962bacce099602509730cd5bb1afc721f439d 9f5192eb-239c-11ed-92af-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=159379 https://www.sciencedirect.com/science/article/pii/S0143416021001573 1 27709c06-239c-11ed-92af-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=159377 Medicinska fakulteta 0 0 0