Neurotoxic phospholipases directly affect synaptic vesicle function |
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Authors: | Treppmann Philipp Brunk Irene Afube Terence Richter Karin Ahnert-Hilger Gudrun |
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Affiliation: | AG Funktionelle Zellbiologie, Institut für Integrative Neuroanatomie, Charité Centrum 2 für Grundlagenmedizin, Berlin, Germany. |
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Abstract: | Snake neurotoxic phospholipases (SPAN) exclusively affect pre-synaptic nerve terminals where they lead to a block of neurotransmission by not fully understood mechanisms. Here, we report that the SPANs, taipoxin and paradoxin, in nanomolar concentrations directly dissociate the synaptophysin/synaptobrevin (Syp/Syb) complex on isolated synaptic vesicles in the presence of synaptosomal cytosol. The phospholipase activity of SPANs depends on Ca(2+) but the dissociation of the Syp/Syb complex does not require Ca(2+). Ca(2+) (100 μM free) alone also dissociates the Syp/Syb complex in the presence of cytosol. Treatment with SPANs disturbs the lipid raft association of synaptophysin and synaptobrevin comparable to cholesterol depletion by β-methyl-cyclodextrin while Ca(2+) alone has no effect. SPANs but not Ca(2+) directly inhibit vesicular uptake of serotonin and glutamate. It is concluded that SPANs directly affect vesicular properties independent from their Ca(2+) -dependent phospholipase activity. SPANs and Ca(2+) dissociate the Syp/Syb complex as a prerequisite for exocytosis. SPANs also prevent the filling of synaptic vesicles thereby adding to the inhibition of neurotransmission. |
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Keywords: | Ca2+ neurotoxic phospholipases synaptic vesicles synaptophysin/synaptobrevin complex vesicular neurotransmitter transporter |
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