Receptor Botulinum neurotoxin

Bullens, R. W., O Hanlon, G. M., Wagner, E. etal. Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function. /. Neurosci. 22 6876-6884, 2002. 

Remarkably, SV2 also appears to be the cellular receptor for botulinum neurotoxin A (Dong et al., 2006). In particular, a segment of the large lumenal loop binds to the toxin, and all of the SV2 isoforms appear capable of serving as receptors. Thus, levetiracetam, even if it is bound to the same site as the toxin, seems unlikely to protect against poisoning since it interacts only with SV2A. 

LaUi G, Bohnert S, Deinhardt K, Verastegui C, Schiavo G (2003) The journey of tetanus and botulinum neurotoxins in neurons. Trends Microbiol 11 431-7 Lambeau G, Lazdunski M (1999) Receptors for a growing family of secreted phospholipases A2. Trends Pharmacol Sd 20 162-70... 

Montecucco C, Schiavo G, Tugnoli V, de Grandis D (1996) Botulinum neurotoxins mechanism of action and therapeutic applications. Mol Med Today 2 418-24 Montecucco C, Rossetto O, Schiavo G (2004) Presynaptic receptor arrays for clostridial neurotoxins. Trends Microbiol 12 442-6... 

Rummel A, Eichner T, Weil T, Karnath T, Gutcaits A et al. (2007) Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept. Proc Natl Acad Sci U S A 104 359-64... 

Jin, R., Rummel, A., Binz, T., Brunger, A.T. (2006). Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature 444 1092-5. 

Middlebrook JL. (1989) Cell surface receptors for protein toxins. In Botulinum neurotoxin and tetanus toxin ( Simpson LL, ed) San Diego Academic Press. 

Chai, Q., Arndt, J.W., Dong, M., Tepp, W.H., Johnson, E.A., Chapman, E.R., and Stevens, R.C. 2006. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 444 1090-1100. 

Middlebrook, J.L., Cell surface receptors for protein toxins, m Botulinum Neurotoxins and Tetanus Toxin, Simpson, L.L., Ed., Academic Press, New York, 1989, chap. 5. 

Li, L. and Singh, B.R., Isolation of synaptotagmin as a receptor for types A and E botulinum neurotoxin and analysis of their comparative binding using a new microtiter plate assay, J. Nat. Toxins, 7, 215, 1998. 

Amperometry at single PC 12 cells has also been used in conjunction with a genetic cell transfection protocol to examine the effects of toxin expression on basal and evoked exocytosis. PC 12 cells have been transfected with the specific endoprotease Botulinum neurotoxin Cl light chain (BoNT/Cl), which cleaves the proteins syntaxin and SNAP-25 [5], The molecular dissection of the mechanisms underlying exocytosis has been motivated by the SNARE hypothesis, which postulates that exocytosis requires the assembly of the plasma membrane proteins syntaxin 1, SNAP-25, and the vesicle associated membrane protein (VAMP) into a complex [5], This SNARE complex then acts as a receptor for cytosolic components of the proposed fusion machinery. Direct evidence for the role of the SNARE proteins in neurotransmission comes from molecular genetic studies in which syntaxin and VAMP have been shown to be required for neurotransmission in Drosophila [47 9] and Caenorhabditis elegans [50,51]. To assess the effects of the disruption of SNARE proteins on exocytosis in PC 12 cells, amperometry has been used in conjunction with a genetic cell transfection assay to establish a... 

Muraro L, Tosatto S, Motterlini L, Rossetto O, Montecucco C. The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane. Biochem Biophys Res Common. 2009 380(l) 76-80. 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

Nishiki t Kamata Y, Nemoto Y et al. (1994) Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J. Biol. Chem. 269 10498-503. 

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