Similar oxysterols may lead to opposite effects on synaptic transmission: Olesoxime versus 5α-cholestan-3-one at the frog neuromuscular junction.
Cholesterol oxidation products frequently have a high biological activity. In the present study, we have used microelectrode recording of end plate currents and FM-based optical detection of synaptic vesicle exo-endocytosis to investigate the effects of two structurally similar oxysterols, olesoxime (cholest-4-en-3-one, oxime) and 5ɑ-cholestan-3-one (5ɑCh3), on neurotransmission at the frog neuromuscular junction. Olesoxime is an exogenous, potentially neuroprotective, substance and 5ɑCh3 is an intermediate product in cholesterol metabolism, which is elevated in the case of cerebrotendinous xanthomatosis. We found that olesoxime slightly increased evoked neurotransmitter release in response to a single stimulus and significantly reduced synaptic depression during high frequency activity. The last effect was due to an increase in both the number of synaptic vesicles involved in exo-endocytosis and the rate of synaptic vesicle recycling. In contrast, 5ɑCh3 reduced evoked neurotransmitter release during the low- and high frequency synaptic activities. The depressant action of 5ɑCh3 was associated with a reduction in the number of synaptic vesicles participating in exo- and endocytosis during high frequency stimulation, without a change in rate of the synaptic vesicle recycling. Of note, olesoxime increased the staining of synaptic membranes with the B-subunit of cholera toxin and the formation of fluorescent ganglioside GM1 clusters, and decreased the fluorescence of 22-NBD-cholesterol, while 5ɑCh3 had the opposite effects, suggesting that the two oxysterols have different effects on lipid raft stability. Taken together, these data show that these two structurally similar oxysterols induce marked different changes in neuromuscular transmission which are related with the alteration in synaptic vesicle cycle.
Department of Normal Physiology, Kazan State Medical University, Kazan 420012, Russia.
M R
MR
Kasimov
Department of Normal Physiology, Kazan State Medical University, Kazan 420012, Russia.
G F
GF
Zakyrjanova
Department of Normal Physiology, Kazan State Medical University, Kazan 420012, Russia.
A R
AR
Giniatullin
Department of Normal Physiology, Kazan State Medical University, Kazan 420012, Russia.
A L
AL
Zefirov
Department of Normal Physiology, Kazan State Medical University, Kazan 420012, Russia. Electronic address: fysio@rambler.ru.
A M
AM
Petrov
D000818:Animals; D002772:Cholera Toxin / Q000737:chemistry; D002776:Cholestanes / Q000494:pharmacology*; D002783:Cholestenones / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives / Q000737:chemistry; D021962:Membrane Microdomains / Q000187:drug effects; D008839:Microelectrodes; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D011895:Rana ridibunda; D013194:Staining and Labeling; D009435:Synaptic Transmission / Q000187:drug effects*; D013572:Synaptic Vesicles / Q000187:drug effects; D046509:Tissue Culture Techniques
D002776:Cholestanes; D002783:Cholestenones; C502266:ganglioside GM1alpha; D005677:G(M1) Ganglioside; D002772:Cholera Toxin; C522838:olesoxime; C007123:coprostanone
5ɑ-Cholestan-3-one; Neuromuscular junction; Neurotransmitter release; Olesoxime; Synaptic vesicle cycle