Abstract
How the widely used botulinum neurotoxin A (BoNT/A) recognizes and enters neurons is poorly understood. We found that BoNT/A enters neurons by binding to the synaptic vesicle protein SV2 (isoforms A, B, and C). Fragments of SV2 that harbor the toxin interaction domain inhibited BoNT/A from binding to neurons. BoNT/A binding to SV2A and SV2B knockout hippocampal neurons was abolished and was restored by expressing SV2A, SV2B, or SV2C. Reduction of SV2 expression in PC12 and Neuro-2a cells also inhibited entry of BoNT/A, which could be restored by expressing SV2 isoforms. Finally, mice that lacked an SV2 isoform (SV2B) displayed reduced sensitivity to BoNT/A. Thus, SV2 acts as the protein receptor for BoNT/A.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Botulinum Toxins, Type A / metabolism*
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Botulinum Toxins, Type A / toxicity
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Cell Line
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Cells, Cultured
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Endocytosis
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Hippocampus / cytology
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Membrane Glycoproteins / chemistry
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neuromuscular Junction / metabolism
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Neurons / metabolism*
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PC12 Cells
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Protein Binding
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Structure, Tertiary
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R-SNARE Proteins / metabolism
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Rats
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Synaptic Vesicles / metabolism*
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Synaptotagmins / metabolism
Substances
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Membrane Glycoproteins
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Nerve Tissue Proteins
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Protein Isoforms
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R-SNARE Proteins
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Sv2a protein, mouse
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Sv2a protein, rat
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Synaptotagmins
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Botulinum Toxins, Type A