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Published online December 24, 2007
doi:10.1083/jcb.200707184
The Journal of Cell Biology, Vol. 179, No. 7, 1511-1522
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Dong et al.
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Article

 Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons

Min Dong1, William H. Tepp2, Huisheng Liu1, Eric A. Johnson2, and Edwin R. Chapman1

1 Howard Hughes Medical Institute, Department of Physiology, and 2 Department of Food Microbiology and Toxicology, University of Wisconsin, Madison, WI 53706

Correspondence to Edwin R. Chapman: chapman{at}physiology.wisc.edu

Botulinum neurotoxins (BoNTs) target presynaptic nerve terminals by recognizing specific neuronal surface receptors. Two homologous synaptic vesicle membrane proteins, synaptotagmins (Syts) I and II, bind toxins BoNT/B and G. However, a direct demonstration that Syts I/II mediate toxin binding and entry into neurons is lacking. We report that BoNT/B and G fail to bind and enter hippocampal neurons cultured from Syt I knockout mice. Wild-type Syts I and II (but not Syt I loss-of-function toxin-binding domain mutants) restored binding and entry of BoNT/B and G in Syt I–null neurons, thus demonstrating that Syts I/II are protein receptors for BoNT/B and G. Furthermore, mice lacking complex gangliosides exhibit reduced sensitivity to BoNT/G, and binding and entry of BoNT/A, B, and G into hippocampal neurons lacking gangliosides is diminished. These data suggest that gangliosides are the shared coreceptor for BoNT/A, B, and G, supporting a double-receptor model for these three BoNTs for which the protein receptors are known.

Abbreviations used in this paper: BoNT, botulinum neurotoxin; DIV, days in vitro; KO, knockout; PSG, polysialioganglioside; Syb, synaptobrevin; Syp, synaptophysin; Syt, synaptotagmin; TeNT, tetanus neurotoxin; WT, wild type.


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