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First published online 29 June 2004
doi: 10.1242/jcs.01218
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Research Article |
1 Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy
2 Molecular NeuroPathoBiology Laboratory, Cancer Research UK, London Research Institute, 61 Lincoln's Inn Fields, London, WC2A 3PX, UK
3 Department of Neuroscience, S. Raffaele Scientific Institute and `Vita-Salute' University, Via Olgettina 58, 20132 Milan, Italy
* Author for correspondence (e-mail: ornella.rossetto{at}unipd.it)
Accepted 11 March 2004
The mechanisms of action of four snake presynaptic phospholipase A2 neurotoxins were investigated in cultured neurons isolated from various parts of the rat brain. Strikingly, physiological concentrations of notexin, ß-bungarotoxin, taipoxin or textilotoxin induced a dose-dependent formation of discrete bulges at various sites of neuronal projections. Neuronal bulging was paralleled by the redistribution of the two synaptic vesicle markers synaptophysin I (SypI) and vesicle-attached membrane protein 2 (VAMP2) to the bulges, and by the exposure of the luminal domain of synaptotagmin on the cell surface. These neurotoxins induced glutamate release from cultured neurons similarly to the known evoked release of acetylcholine from neuromuscular junctions. In addition, partial fragmentation of F-actin and neurofilaments was observed in neurons, but not in astrocytes. These findings indicate that these snake presynaptic neurotoxins act with by same mechanism and that the observed phenotype results from the fusion of synaptic vesicles with the plasma membrane not balanced by an adequate membrane retrieval. These changes closely resemble those occurring at neuromuscular junctions of intoxicated animals and fully qualify these primary neuronal cultures as pertinent models for studying the molecular mode of action of these neurotoxins.
Key words: Snake presynaptic neurotoxins, Phospholipase A2, Synaptic vesicle recycling, Neurotransmitter release, Synaptic vesicles
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