Olesoxime,a cholesterol-like neuroprotectant restrains synaptic vesicle exocytosis in the mice motor nerve terminals: Possible role of VDACs |
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| Affiliation: | 1. Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center “Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, box 30, Kazan 420111, Russia;2. Institute of Neuroscience, Kazan State Medial University, 49 Butlerova Street, Kazan 420012, Russia;1. Department of Anesthesiology, Washington University in St. Louis, MO 63110, USA;2. Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, MO 63110, USA;3. Department of Developmental Biology, Washington University in St. Louis, MO 63110, USA;4. Department of Psychiatry, Washington University in St. Louis, MO 63110, USA;5. Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, MO 63110, USA;6. Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;7. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;8. Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA |
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| Abstract: | Olesoxime is a cholesterol-like neuroprotective compound that targets to mitochondrial voltage dependent anion channels (VDACs). VDACs were also found in the plasma membrane and highly expressed in the presynaptic compartment. Here, we studied the effects of olesoxime and VDAC inhibitors on neurotransmission in the mouse neuromuscular junction. Electrophysiological analysis revealed that olesoxime suppressed selectively evoked neurotransmitter release in response to a single stimulus and 20 Hz activity. Also olesoxime decreased the rate of FM1–43 dye loss (an indicator of synaptic vesicle exocytosis) at low frequency stimulation and 20 Hz. Furthermore, an increase in extracellular Cl− enhanced the action of olesoxime on the exocytosis and olesoxime increased intracellular Cl− levels. The effects of olesoxime on the evoked synaptic vesicle exocytosis and [Cl−]i were blocked by membrane-permeable and impermeable VDAC inhibitors. Immunofluorescent labeling pointed on the presence of VDACs on the synaptic membranes. Rotenone-induced mitochondrial dysfunction perturbed the exocytotic release of FM1–43 and cell-permeable VDAC inhibitor (but not olesoxime or impermeable VDAC inhibitor) partially mitigated the rotenone-driven alterations in the FM1–43 unloading and mitochondrial superoxide production. Thus, olesoxime restrains neurotransmission by acting on plasmalemmal VDACs whose activation can limit synaptic vesicle exocytosis probably via increasing anion flux into the nerve terminals. |
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