Abstract
Quantal transmitter release from nerves is inhibited by all seven serotypes (A–G) of botulinum neurotoxin (BoNT), with some subtle but functional differences. Commonalities and dissimilarities in these proteins, and new recombinant forms, are highlighted in terms of their multiple activities and domains responsible for binding to the neuronal acceptors, subsequent endocytosis, translocation and proteolytic inactivation of intracellular soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) culminating in the blockade of neuro-exocytosis lasting for weeks or months. The neurotoxins bind to dual acceptors, gangliosides and intra-lumenal regions of vesicular proteins, and co-traffic into neurons. Subsequently, their proteases pass to the cytosol via a channel created in the endosomal limiting membrane and cleave distinct bonds in the substrate SNARE(s). Modification of these targets is responsible for their characteristic pharmacological activities. The prolonged duration of type A seems attributable to an identified stabilisation motif that extends the longevity of its protease. BoNTs have proved instrumental in deciphering a molecular basis for regulated exocytosis; now, emerging knowledge is helping to explain why synchronisation of released quanta of transmitter is perturbed by certain serotypes (/B, /D and /F) and not others (/A, /C1 and /E). Novel chimeras created by protein engineering are endowed with advantageous features of two serotypes for targeting sensory neurons and alleviating inflammatory pain (LC/E-BoTIM/A). Likewise, an innocuous mutant of /B (BoTIM/B) fused to core streptavidin (CS-BoTIM/B) has been exploited for guiding molecular cargo and viral vectors into nerve cells. These novel discoveries exemplify the versatility of BoNT in targeting and delivering therapeutics into neurons.
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Dolly JO, Lawrence GW, Meng J, Wang J, Ovsepian SV (2009) Neuro-exocytosis: botulinum toxins as inhibitory probes and versatile therapeutics. Curr Opin Pharmacol 9:326–335
Popoff MR, Bouvet P (2009) Clostridial toxins. Future Microbiol 4:1021–1064
Dolly JO, Wang J, Zurawski TH, Meng J (2011) Novel therapeutics based on recombinant botulinum neurotoxins to normalize the release of transmitters and pain mediators. FEBS J 278:4454–4466
Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC (1998) Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol 5:898–902
Schiavo G, van der Goot FG (2001) The bacterial toxin toolkit. Nat Rev Mol Cell Biol 2:530–537
Simpson LL (1986) Molecular pharmacology of botulinum toxin and tetanus toxin. Annu Rev Pharmacol Toxicol 26:427–453
Dolly JO, Black J, Williams RS, Melling J (1984) Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature 307:457–460
Black JD, Dolly JO (1986) Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves. J Cell Biol 103:521–534
Black JD, Dolly JO (1986) Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J Cell Biol 103:535–544
Hughes R, Whaler BC (1962) Influence of nerve-ending activity and of drugs on the rate of paralysis of rat diaphragm preparations by Cl. botulinum type A toxin. J Physiol 160:221–233
Montal M (2010) Botulinum neurotoxin: a marvel of protein design. Annu Rev Biochem 79:591–617
Poulain B et al (1988) Neurotransmitter release is blocked intracellularly by botulinum neurotoxin, and this requires uptake of both toxin polypeptides by a process mediated by the larger chain. Proc Natl Acad Sci U S A 85:4090–4094
McInnes C, Dolly JO (1990) Ca2( + )-dependent noradrenaline release from permeabilised PC12 cells is blocked by botulinum neurotoxin A or its light chain. FEBS Lett 261:323–326
McMahon HT et al (1992) Tetanus toxin and botulinum toxins type A and B inhibit glutamate, gamma-aminobutyric acid, aspartate, and met-enkephalin release from synaptosomes. Clues to the locus of action. J Biol Chem 267:21338–21343
Foster KA (2009) Engineered toxins: new therapeutics. Toxicon 54:587–592
Goodnough MC et al (2002) Development of a delivery vehicle for intracellular transport of botulinum neurotoxin antagonists. FEBS Lett 513:163–168
Weller U, Dauzenroth ME, Gansel M, Dreyer F (1991) Cooperative action of the light chain of tetanus toxin and the heavy chain of botulinum toxin type A on the transmitter release of mammalian motor endplates. Neurosci Lett 122:132–134
Zhang P et al (2009) An efficient drug delivery vehicle for botulism countermeasure. BMC Pharmacol 9:12
Bowers WJ, Breakefield XO, Sena-Esteves M (2011) Genetic therapy for the nervous system. Hum Mol Genet 20:R28–R41
Meininger V (2011) ALS, what new 144 years after Charcot? Arch Ital Biol 149:29–37
Nanou A, Azzouz M (2009) Gene therapy for neurodegenerative diseases based on lentiviral vectors. Prog Brain Res 175:187–200
Schlachetzki F, Zhang Y, Boado RJ, Pardridge WM (2004) Gene therapy of the brain: the trans-vascular approach. Neurology 62:1275–1281
Stanzione P, Tropepi D (2011) Drugs and clinical trials in neurodegenerative diseases. Ann Ist Super Sanita 47:49–54
Li Y et al (2001) Recombinant forms of tetanus toxin engineered for examining and exploiting neuronal trafficking pathways. J Biol Chem 276:31394–31401
Pellett S et al (2011) Neuronal targeting, internalization, and biological activity of a recombinant atoxic derivative of botulinum neurotoxin A. Biochem Biophys Res Commun 405:673–677
Hill KK et al (2007) Genetic diversity among botulinum neurotoxin-producing Clostridial strains. J Bacteriol 189:818–832
Moriishi K et al (1996) Mosaic structures of neurotoxins produced from Clostridium botulinum types C and D organisms. Biochim Biophys Acta 1307:123–126
Dolly JO, Lande S, Wray DW (1987) The effects of in vitro application of purified botulinum neurotoxin at mouse motor nerve terminals. J Physiol 386:475–484
Morbiato L et al (2007) Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C. Eur J Neurosci 25:2697–2704
Molgo J, Siegel LS, Tabti N, Thesleff S (1989) A study of synchronization of quantal transmitter release from mammalian motor endings by the use of botulinal toxins type A and D. J Physiol 411:195–205
Sellin LC, Kauffman JA, DasGupta BR (1983) Comparison of the effects of botulinum neurotoxin types A and E at the rat neuromuscular junction. Medical Biology 61:120–125
Sellin LC, Thesleff S, Dasgupta BR (1983) Different effects of types A and B botulinum toxin on transmitter release at the rat neuromuscular junction. Acta Physiol Scand 119:12733
Kauffman JA, Way JF Jr, Siegel LS, Sellin LC (1985) Comparison of the action of types A and F botulinum toxin at the rat neuromuscular junction. Toxicol Appl Pharmacol 79:211–217
Coffield JA et al (1997) In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmacologic and molecular biologic approaches. J Pharmacol Exp Ther 280:1489–1498
Comella JX, Molgo J, Faille L (1993) Sprouting of mammalian motor nerve terminals induced by in vivo injection of botulinum type-D toxin and the functional recovery of paralysed neuromuscular junctions. Neurosci Lett 153:61–64
Molgo J, Dasgupta BR, Thesleff S (1989) Characterization of the actions of botulinum neurotoxin type E at the rat neuromuscular junction. Acta Physiol Scand 137:497–501
Simpson LL (1986) A preclinical evaluation of aminopyridines as putative therapeutic agents in the treatment of botulism. Infect Immun 52:858–862
Adler M, Macdonald DA, Sellin LC, Parker GW (1996) Effect of 3,4-diaminopyridine on rat extensor digitorum longus muscle paralyzed by local injection of botulinum neurotoxin. Toxicon 34:237–249
Meunier FA, Lisk G, Sesardic D, Dolly JO (2003) Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are dictated by the sites of SNAP-25 truncation. Mol Cell Neurosci 22:454–466
Wang J et al (2008) Novel chimeras of botulinum neurotoxins A and E unveil contributions from the binding, translocation, and protease domains to their functional characteristics. J Biol Chem 283:16993–17002
Eleopra R, Tugnoli V, Rossetto O, Montecucco C, De Grandis D (1997) Botulinum neurotoxin serotype C: a novel effective botulinum toxin therapy in human. Neurosci Lett 224:91–94
Montecucco C, Molgo J (2005) Botulinal neurotoxins: revival of an old killer. Curr Opin Pharmacol 5:274–279
Sloop RR, Cole BA, Escutin RO (1997) Human response to botulinum toxin injection: type B compared with type A. Neurology 49:189–194
de Paiva A, Meunier FA, Molgo J, Aoki KR, Dolly JO (1999) Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A 96:3200–3205
Dong M et al (2006) SV2 is the protein receptor for botulinum neurotoxin A. Science 312:592–596
Mahrhold S, Rummel A, Bigalke H, Davletov B, Binz T (2006) The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 580:20114
Stenmark P, Dupuy J, Imamura A, Kiso M, Stevens RC (2008) Crystal structure of botulinum neurotoxin type A in complex with the cell surface co-receptor GT1b-insight into the toxin-neuron interaction. PLoS Pathog 4:e1000129
Dong M et al (2003) Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J Cell Biol 162:1293–1303
Nishiki T et al (1994) Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J Biol Chem 269:10498–10503
Dong M, Tepp WH, Liu H, Johnson EA, Chapman ER (2007) Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons. J Cell Biol 179:1511–1522
Peng L, Tepp WH, Johnson EA, Dong M (2011) Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLoS Pathog 7:e1002008
Dong M et al (2008) Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol Biol Cell 19:5226–5237
Rummel A et al (2009) Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. J Neurochem 110:1942–1954
Fu Z, Chen C, Barbieri JT, Kim JJ, Baldwin MR (2009) Glycosylated SV2 and gangliosides as dual receptors for botulinum neurotoxin serotype F. BioChemistry 48:5631–5641
Rummel A, Karnath T, Henke T, Bigalke H, Binz T (2004) Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. J Biol Chem 279:30865–30870
Simpson LL (1982) The interaction between aminoquinolines and presynaptically acting neurotoxins. J Pharmacol Exp Ther 222:43–48
Simpson LL, Coffield JA, Bakry N (1994) Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins. J Pharmacol Exp Ther 269:256–262
Lawrence G, Wang J, Chion CK, Aoki KR, Dolly JO (2007) Two protein trafficking processes at motor nerve endings unveiled by botulinum neurotoxin E. J Pharmacol Exp Ther 320:410–418
de Paiva A et al (1993) A role for the interchain disulfide or its participating thiols in the internalization of botulinum neurotoxin A revealed by a toxin derivative that binds to ectoacceptors and inhibits transmitter release intracellularly. J Biol Chem 268:20838–20844
Fischer A, Montal M (2007) Single molecule detection of intermediates during botulinum neurotoxin translocation across membranes. Proc Natl Acad Sci U S A 104:10447–10452
Schiavo G et al (1993) Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett 335:99–103
Blasi J et al (1993) Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365:160–163
Schiavo G et al (1992) Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359:832–835
Blasi J et al (1993) Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. EMBO J 12:4821–4828
Schiavo G, Shone CC, Bennett MK, Scheller RH, Montecucco C (1995) Botulinum neurotoxin type C cleaves a single Lys-Ala bond within the carboxyl-terminal region of syntaxins. J Biol Chem 270:10566–10570
Foran P, Lawrence GW, Shone CC, Foster KA, Dolly JO (1996) Botulinum neurotoxin C1 cleaves both syntaxin and SNAP-25 in intact and permeabilized chromaffin cells: correlation with its blockade of catecholamine release. BioChemistry 35:2630–2636
Williamson LC, Halpern JL, Montecucco C, Brown JE, Neale EA (1996) Clostridial neurotoxins and substrate proteolysis in intact neurons: botulinum neurotoxin C acts on synaptosomal-associated protein of 25 kDa. J Biol Chem 271:7694–7699
Yamasaki S et al (1994) Cleavage of members of the synaptobrevin/VAMP family by types D and F botulinal neurotoxins and tetanus toxin. J Biol Chem 269:12764–12772
Schiavo G et al (1993) Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E. J Biol Chem 268:23784–23787
Binz T et al (1994) Proteolysis of SNAP-25 by types E and A botulinal neurotoxins. J Biol Chem 269:1617–1620
Schiavo G, Shone CC, Rossetto O, Alexander FC, Montecucco C (1993) Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J Biol Chem 268:11516–11519
Schiavo G et al (1994) Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala-Ala peptide bond. J Biol Chem 269:20213–20216
Yamasaki S et al (1994) Botulinum neurotoxin type G proteolyses the Ala81-Ala82 bond of rat synaptobrevin 2. Biochem Biophys Res Commun 200:829–835
Foran PG et al (2003) Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons. J Biol Chem 278:1363–1371
Keller JE, Neale EA, Oyler G, Adler M (1999) Persistence of botulinum neurotoxin action in cultured spinal cord cells. FEBS Lett 456:137–142
Stanley EF, Drachman DB (1983) Botulinum toxin blocks quantal but not non-quantal release of ACh at the neuromuscular junction. Brain Res 261:172–175
Humeau Y, Doussau F, Grant NJ, Poulain B (2000) How botulinum and tetanus neurotoxins block neurotransmitter release. Biochimie 82:427–446
Molgo J et al (1990) Presynaptic actions of botulinal neurotoxins at vertebrate neuromuscular junctions. J Physiol (Paris) 84:152–166
Jankovic J et al (2009) Botulinum toxin: therapeutic clinical practice and science. Saunders Elsevier, Philadelphia
Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M (2008) Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci 28:3689–3696
Lawrence GW, Ovsepian SV, Wang J, Aoki KR, Dolly JO (2012) Extravesicular intraneuronal migration of internalized botulinum neurotoxins without detectable inhibition of distal neurotransmission. Biochem J 441:443–452
Wang J et al (2011) A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic. J Biol Chem 286:637585
Fernandez-Salas E et al (2004) Plasma membrane localization signals in the light chain of botulinum neurotoxin. Proc Natl Acad Sci U S A 101:3208–3213
Aoki KR (2001) A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice. Toxicon 39:1815–1820
Yamauchi PS, Lowe NJ (2004) Botulinum toxin types A and B comparison of efficacy, duration, and dose-ranging studies for the treatment of facial rhytides and hyperhidrosis. Clin Dermatol 22:34–39
Tintner R, Gross R, Winzer UF, Smalky KA, Jankovic J (2005) Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial. Neurology 65:765–767
Dressler D, Hallett M (2006) Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc. Eur J Neurol 13 Suppl 1:11–15
Gassner HG et al (2006) Botulinum toxin to improve facial wound healing: A prospective, blinded, placebo-controlled study. Mayo Clin Proc 81:1023–1028
Takamori S et al (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846
Daniels-Holgate PU, Dolly JO (1996) Productive and non-productive binding of botulinum neurotoxin A to motor nerve endings are distinguished by its heavy chain. J Neurosci Res 44:263–271
Black JD, Dolly JO (1987) Selective location of acceptors for botulinum neurotoxin A in the central and peripheral nervous systems. Neuroscience 23:767–779
Williams RS, Tse CK, Dolly JO, Hambleton P, Melling J (1983) Radioiodination of botulinum neurotoxin type A with retention of biological activity and its binding to brain synaptosomes. Eur J Biochem 131:437–445
Evans DM et al (1986) Botulinum neurotoxin type B. Its purification, radioiodination and interaction with rat-brain synaptosomal membranes. Eur J Biochem 154:409–416
Wadsworth JD et al (1990) Botulinum type F neurotoxin. Large-scale purification and characterization of its binding to rat cerebrocortical synaptosomes. Biochem J 268:123–128
Schiavo G, Matteoli M, Montecucco C (2000) Neurotoxins affecting neuroexocytosis. Physiol Rev 80:717–766
Brunger AT, Rummel A (2009) Receptor and substrate interactions of clostridial neurotoxins. Toxicon 54:550–560
Simpson LL, DasGupta BR (1983) Botulinum neurotoxin type E studies on mechanism of action and on structure-activity relationships. J Pharmacol Exp Ther 224:135–140
Fischer A, Mushrush DJ, Lacy DB, Montal M (2008) Botulinum neurotoxin devoid of receptor binding domain translocates active protease. PLoS Pathog 4:e1000245
Niemann H, Blasi J, Jahn R (1994) Clostridial neurotoxins: new tools for dissecting exocytosis. Trends Cell Biol 4:179–185
de Paiva A et al (1993) Botulinum A like type B and tetanus toxins fulfils criteria for being a zinc-dependent protease. J Neurochem 61:2338–2341
Meng J et al (2009) Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci 29:4981–4992
Meng J, Wang J, Lawrence G, Dolly JO (2007) Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci 120:2864–2874
Hayashi T et al (1994) Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO J 13:5051–5061
Wang D et al (2011) Syntaxin requirement for Ca2+-triggered exocytosis in neurons and endocrine cells demonstrated with an engineered neurotoxin. Biochemistry 50:2711–2713
Geppert M et al (1994) Synaptotagmin I: a major Ca2+sensor for transmitter release at a central synapse. Cell 79:717–727
Reim K et al (2001) Complexins regulate a late step in Ca2+-dependent neurotransmitter release. Cell 104:71–81
Yang X, Kaeser-Woo YJ, Pang ZP, Xu W, Sudhof TC (2010) Complexin clamps asynchronous release by blocking a secondary Ca(2 + ) sensor via its accessory alpha helix. Neuron 68:907–920
Chapman ER (2008) How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem 77:615–641
Chen X et al (2002) Three-dimensional structure of the complexin/SNARE complex. Neuron 33:397–409
Kummel D et al (2011) Complexin cross-links prefusion SNAREs into a zigzag array. Nat Struct Mol Biol 18:927–933
Krishnakumar SS et al (2011) A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion. Nat Struct Mol Biol 18:934–940
Yao J, Gaffaney JD, Kwon SE, Chapman ER (2011) Doc2 is a Ca2+sensor required for asynchronous neurotransmitter release. Cell 147:666–677
Washbourne P et al (2002) Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis. Nat Neurosci 5:19–26
Naumann M, Jost WH, Toyka KV (1999) Botulinum toxin in the treatment of neurological disorders of the autonomic nervous system. Arch Neurol 56:914–916
O’Leary VB et al (2011) Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons. Gene Ther 18:656–665
Sano T, Pandori MW, Chen X, Smith CL, Cantor CR (1995) Recombinant core streptavidins. A minimum-sized core streptavidin has enhanced structural stability and higher accessibility to biotinylated macromolecules. J Biol Chem 270:28204–28209
Edupuganti OP et al (2012) Targeted delivery into motor nerve terminals of inhibitors for SNARE-cleaving proteases via liposomes coupled to an atoxic botulinum neurotoxin. FEBS J 279:2555–2567
Mastromarino P, Conti C, Goldoni P, Hauttecoeur B, Orsi N (1987) Characterization of membrane components of the erythrocyte involved in vesicular stomatitis virus attachment and fusion at acidic pH. J Gen Virol 68(Pt 9):2359-2369
Kuder T, Szczurkowski A, Kuchinka J, Nowak E (2003) The AChE-positive ganglia in the trachea and bronchi of the cat. Folia Morphol (Warsz) 62:99-106
Kusindarta DL, Atoji Y, Yamamoto Y (2004) Nerve plexuses in the trachea and extrapulmonary bronchi of the rat. Arch Histol Cytol 67:41–55
Koticha DK, McCarthy EE, Baldini G (2002) Plasma membrane targeting of SNAP-25 increases its local concentration and is necessary for SNARE complex formation and regulated exocytosis. J Cell Sci 115:3341–3351
O’Sullivan GA, Mohammed N, Foran PG, Lawrence GW, Oliver DJ (1999) Rescue of exocytosis in botulinum toxin A-poisoned chromaffin cells by expression of cleavage-resistant SNAP-25. Identification of the minimal essential C-terminal residues. J Biol Chem 274:36897–36904
Delgado-Martinez I, Nehring RB, Sorensen JB (2007) Differential abilities of SNAP-25 homologs to support neuronal function. J Neurosci 27:9380–9391
Mochida S, Sheng ZH, Baker C, Kobayashi H, Catterall WA (1996) Inhibition of neurotransmission by peptides containing the synaptic protein interaction site of N-type Ca2 + channels. Neuron 17:781–788
Acknowledgements
This research was supported by a Principal Investigator grant (to J.O.D.) from Science Foundation Ireland, a contract for basic research from Allergan Inc., a HDTRA contract (no. 1-07-C-0034) from the US Government, a commercialisation award from Enterprise Ireland, and funding under the Programme for Research in Third Level Institutions (PRTLI) Cycle 4. The PRTLI is co-funded through the European Regional Development Fund (ERDF), part of the European Union Structural Funds Programme 2007–2013. Group members (Drs. J. Wang, J. Meng and T. Zurawski) are thanked for their data cited in this review.
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Dolly, J., O’Leary, V., Lawrence, G., Ovsepian, S. (2014). Pharmacology of Botulinum Neurotoxins: Exploitation of Their Multifunctional Activities as Transmitter Release Inhibitors and Neuron-Targeted Delivery Vehicles. In: Foster, K. (eds) Molecular Aspects of Botulinum Neurotoxin. Current Topics in Neurotoxicity, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9454-6_2
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