Botulinum toxin type A (BoNT/A), a disulfide bonded heavy chain (HC) - light chain (LC) heterodimer ("dichain"), enters the gut typically as a result of consuming contaminated food (Hatheway 1995), as a complex with nontoxic nonhemagglutinin protein (NTNHA, encoded by the C. botulinum ntnha gene) and multiple copies of three hemagglutinin proteins (HA, encoded by the C. botulinum ha17, ha34, and ha70 genes) (Lee et al. 2013). The complex protects the toxin from degradation in the gut and mediates its association with the gut epithelium and transcytosis to enter the circulation. Recent studies in vitro raise the possibility that the toxin may also directly disrupt the basolateral membrane of the gut epithelium (Fujinaga et al. 2013). Circulating toxin molecules associate with gangliosides and synaptic vesicle protein 2 (SV2) exposed by exocytosis at a synapse of a target neuron in the neuromuscular junction (Yowler& Schengrund 2004; Dong et al. 2006). Vesicle recycling brings the toxin into the neuron where the vesicle is acidified (Sudhoff 2004). The lowered pH induces a conformational change in the toxin: its HC forms a passage in the vesicle membrane through which its LC is extruded into the neuronal cytosol and released by reduction of the HC - LC disulfide bond (Montal 2010). The cytosolic LC then catalyzes the cleavage of synaptosomal associated protein 25 (SNAP25) on the cytosolic face of the neuronal plasma membrane (Binz et al. 1994; Schiavo et al. 1993), thereby inhibiting synaptic vesicle fusion with the plasma membrane and exocytosis.
Dong, M, Yeh, F, Tepp, WH, Dean, C, Johnson, EA, Janz, R, Chapman, ER
Fujinaga, Y, Sugawara, Y, Matsumura, T
Montal, M
Yowler, BC, Schengrund, CL
Schiavo, G, Santucci, A, DasGupta, BR, Mehta, PP, Jontes, J, Benfenati, F, Wilson, MC, Montecucco, C
Südhof, TC
Hatheway, CL
Lee, K, Gu, S, Jin, L, Le, TT, Cheng, LW, Strotmeier, J, Kruel, AM, Yao, G, Perry, K, Rummel, A, Jin, R
Binz, T, Blasi, J, Yamasaki, S, Baumeister, A, Link, E, Südhof, TC, Jahn, R, Niemann, H
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