Journal
JOURNAL OF CELL BIOLOGY
Volume 162, Issue 7, Pages 1293-1303Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200305098
Keywords
synaptotagmin; synaptobrevin; clostridial neurotoxin; neurotoxin receptor; gangliosides
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Funding
- NIAID NIH HHS [AI42226] Funding Source: Medline
- NIGMS NIH HHS [GM 56827, R01 GM056827] Funding Source: Medline
- NIMH NIH HHS [R01 MH061876, MH61876] Funding Source: Medline
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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.
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