Effects of Antiepileptic Agents on Homotypic Fusion of Synaptic Vesicles |
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Authors: | V P Gumenyuk G P Volinets T M Kuchmerovskaya I O Trikash |
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Institution: | 1.Palladin Institute of Biochemistry,National Academy of Sciences of Ukraine,Kyiv,Ukraine |
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Abstract: | We studied the effects of three antiepileptic drugs (AEDs) in a cell-free model system containing isolated synaptic vesicles
(SVs) and cytosolic proteins, which allowed us to reproduce one of the stages of complex exocytosis. Ethosuximide, sodium
valproate, and gabapentin intensified calcium- and Mg2+-ATP-induced fusion of SVs; the effect was indicative of the ability of these agents to influence the processes of simple
and/or complex exocytosis in synaptic connections in the CNS structures. Antiepileptic drugs did not change the intensity
of calcium-dependent fusion of liposomes and SVs treated by proteases. Therefore, the effect of AEDs can be realized via their
interaction with proteins of SVs. After decrease in the level of cholesterol in the membranes of SVs using treatment by methyl-β-
cyclodextrin, the ability of AEDs to activate fusion of SVs remained unchanged. Therefore, the studied AEDs act via proteins
localized beyond the borders of cholesterol-enriched microdomains of the membrane. Drugs that induce convulsions (corazole
and picrotoxin) did not change the characteristics of fusion of SVs under the in vitro action of AEDs. This is indicative of the absence of molecular targets for the above chemoconvulsants in the SV membranes,
as compared with those in the plasma membranes of nerve terminals. According to our experiments, just proteins of SVs are
functional targets for ethosuximide, sodium valproate, and gabapentin providing their anticonvulsant actions. The proposed
model, which allows one to reproduce the membrane fusion, can be successfully used for the testing of drugs influencing a
presynaptic link of synaptic contacts in the CNS. |
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