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© The Rockefeller University Press, 0021-9525/2003/9/1293 $5.00
The Journal of Cell Biology, Volume 162, Number 7, 1293-1303

Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells

¹ Department of Physiology and the Neuroscience Training Program, University of Wisconsin, Madison, Madison, WI 53706
² Department of Food Microbiology and Toxicology, University of Wisconsin, Madison, Madison, WI 53706
³ Metabiologics, Inc., Madison, WI 53719

Address correspondence to E.R. Chapman, Dept. of Physiology, SMI 129, University of Wisconsin, Madison, 1300 University Ave., Madison, WI 53706. Tel.: (608) 263-1762. Fax: (608) 265-5512. email: chapman{at}physiology.wisc.edu

Botulinum neurotoxins (BoNTs) cause botulism by entering neurons and cleaving proteins that mediate neurotransmitter release; disruption of exocytosis results in paralysis and death. The receptors for BoNTs are thought to be composed of both proteins and gangliosides; however, protein components that mediate toxin entry have not been identified. Using gain-of-function and loss-of-function approaches, we report here that the secretory vesicle proteins, synaptotagmins (syts) I and II, mediate the entry of BoNT/B (but not BoNT/A or E) into PC12 cells. Further, we demonstrate that BoNT/B entry into PC12 cells and rat diaphragm motor nerve terminals was activity dependent and can be blocked using fragments of syt II that contain the BoNT/B-binding domain. Finally, we show that syt II fragments, in conjunction with gangliosides, neutralized BoNT/B in intact mice. These findings establish that syts I and II can function as protein receptors for BoNT/B.

Key Words: synaptotagmin; synaptobrevin; clostridial neurotoxin; neurotoxin receptor; gangliosides

Abbreviations used in this paper: BoNT, botulinum neurotoxin; CNT, clostridial neurotoxin; syb, synaptobrevin; syt, synaptotagmin; TeNT, tetanus neurotoxin.

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