Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins) leading to characteristics neurological affections. But many other toxins are multifunctional and recognize a wider range of cell types including neuronal cells. Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins can pass the blood brain barrier and directly act on specific neurons.
References
[1]
Gill, D.M. Bacterial toxins: Lethal amounts. In Toxins and Enzymes; Laskin, A.I., Lechevalier, H.A., Eds.; CRC Press: Cleveland, OH, USA, 1987; Volume 8, pp. 127–135.
[2]
Popoff, M.R. Purification and characterization of Clostridium sordellii lethal toxin and cross-reactivity with Clostridium difficile cytotoxin. Infect. Immun.？1987, 55, 35–43.
[3]
Von Eichel-Streiber, C.; Harperath, U.; Bosse, D.; Hadding, U. Purification of two high molecular weigth toxins of Clostridium difficile which are antigenically related. Microb. Pathogen？1987, 2, 307–318.
[4]
Meng, X.Q.; Kamiya, S.; Yamakawa, K.; Ogura, H.; Nakamura, S. Purification and characterisation of intracellular toxin A of Clostridium difficile. J. Med. Microbiol.？1993, 38, 69–73.
[5]
Burleigh, D.E.; Banks, M.R. Stimulation of intestinal secretion by vasoactive intestinal peptide and cholera toxin. Auton. Neurosci.？2007, 133, 64–75.
[6]
Murthy, V.N.; De Camilli, P. Cell biology of the presynaptic terminal. Annu. Rev. Neurosci.？2003, 26, 701–728.
[7]
Takamori, S.; Holt, M.; Stenius, K.; Lemke, E.A.; Gronborg, M.; Riedel, D.; Urlaub, H.; Schenck, S.; Brugger, B.; Ringler, P.; Muller, S.A.; Rammner, B.; Grater, F.; Hub, J.S.; De Groot, B.L.; Mieskes, G.; Moriyama, Y.; Klingauf, J.; Grubmuller, H.; Heuser, J.; Wieland, F.; Jahn, R. Molecular anatomy of a trafficking organelle. Cell？2006, 127, 831–846.
[8]
Kasai, H. Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function. Trends Neurosci.？1999, 22, 88–93.
Groffen, A.; Friedrich, R.; Brian, E.C.; Ashery, U.; Verhage, M. DOC2A and DOC2B are sensors for neuronal activity with unique calcium-dependent and kinetic properties. J. Neurochem.？2006, 97, 818–833.
[20]
Augustine, G.J. How does calcium trigger neurotransmitter release? Curr. Opin. Neurobiol.？2001, 11, 320–326, doi:10.1016/S0959-4388(00)00214-2. 11399430
[21]
Segev, N. Ypt/rab gtpases: Regulators of protein trafficking. Sci. STKE？2001, 2001, RE11.
[22]
Eitzen, G. Actin remodeling to facilitate membrane fusion. Biochim. Biophys. Acta？2003, 1641, 175–181.
[23]
Bader, M.F.; Doussau, F.; Chasserot-Golaz, S.; Vitale, N.; Gasman, S. Coupling actin and membrane dynamics during calcium-regulated exocytosis: A role for Rho and ARF GTPases. Biochim. Biophys. Acta？2004, 1742, 37–49.
[24]
Hall, A. Rho GTPases and the actin cytoskeleton. Science？1998, 279, 509–514.
[25]
Gasman, S.; Chasserot-Golaz, S.; Malacombe, M.; Way, M.; Bader, M.F. Regulated exocytosis in neuroendocrine cells: A role for subplasmalemmal Cdc42/N -WASP-induced actin filaments. Mol. Biol. Cell？2004, 15, 520–531.
[26]
Li, Q.; Ho, C.S.; Marinescu, V.; Bhatti, H.; Bokoch, G.M.; Ernst, S.A.; Holz, R.W.; Stuenkel, E.L. Facilitation of Ca(2+)-dependent exocytosis by Rac1-GTPase in bovine chromaffin cells. J. Physiol.？2003, 550, 43–145.
[27]
Doussau, F.; Gasman, S.; Humeau, Y.; Vitiello, F.; Popoff, M.R.; Boquet, P.; Bader, M.F.; Poulain, B. A Rho-related GTPase is involved in Ca++-dependent neurotransmitter exocytosis. J. Biol. Chem.？2000, 275, 7764–7770.
[28]
Humeau, Y.; Popoff, M.R.; Kojima, H.; Dousseau, F.; Poulain, B. Rac GTPase plays an essential role in exocytosis by controlling the fusion competence in release sites. J. Neurosci.？2002, 22, 7968–7981.
[29]
Momboisse, F.; Lonchamp, E.; Calco, V.; Ceridono, M.; Vitale, N.; Bader, M.F.; Gasman, S. betaPIX-activated Rac1 stimulates the activation of phospholipase D, which is associated with exocytosis in neuroendocrine cells. J. Cell. Sci.？2009, 122, 798–806.
[30]
Vitale, N.; Chasserot-Golaz, S.; Bailly, Y.; Morinaga, N.; Frohman, M.A.; Bader, M.F. Calcium-regulated exocytosis of dense-core vesicles requires the activation of ADP-ribosylation factor (ARF)6 by ARF nucleotide binding site opener at the plasma membrane. J. Cell. Biol.？2002, 159, 79–89.
[31]
Bielinski, D.F.; Pyun, H.Y.; Linko-Stentz, K.; Macara, I.G.; Fine, R.E. Protein Ral and Rab3a are major GTP-binding proteins of axonal rapid transport and synaptic vesicles and do not redistribute following depolarization stimulated synaptosomal exocytosis. Biochim. Biophys. Acta？1993, 1151, 246–256.
[32]
Polzin, A.; Shipitsin, M.; Goi, T.; Feig, L.A.; Turner, T.J. Ral-GTPase influences the regulation of the readily releasable pool of synaptic vesicles. Mol. Cell Biol.？2002, 22, 1714–1722.
[33]
Luo, J.Q.; Liu, X.; Frankel, P.; Rotunda, T.; Ramos, M.; Flom, J.; Jiang, H.; Feig, L.A.; Morris, A.J.; Kahn, R.A.; Foster, D.A. Functional association between Arf and RalA in active phospholipase D complex. Proc. Natl. Acad. Sci. USA？1998, 95, 3632–3637.
[34]
Choi, W.S.; Kim, Y.M.; Combs, C.; Frohman, M.A.; Beaven, M.A. Phospholipases D1 and D2 regulate different phases of exocytosis in mast cells. J. Immunol.？2002, 168, 5682–5689.
[35]
Humeau, Y.; Vitale, N.; Chasserot-Golaz, S.; Dupont, J.L.; Du, G.; Frohman, M.A.; Bader, M.F.; Poulain, B. A role for phospholipase D1 in neurotransmitter release. Proc. Natl. Acad. Sci. (USA)？2001, 98, 15300–15305.
[36]
Humeau, Y.; Doussau, F.; Popoff, M.R.; Benfenati, F.; Poulain, B. Fast changes in the functional status of release sites during short-term plasticity: Involvement of a frequency-dependent bypass of Rac at Aplysia synapses. J. Physiol.？2007, 583, 983–1004.
[37]
Vitale, N.; Caumont, A.S.; Chasserot-Golaz, S.; Du, G.; Wu, S.; Sciorra, V.A.; Morris, A.J.; Frohman, M.A.; Bader, M.F. Phospholipase D1: A key factor for the exocytic machinery in neuroendocrine cells. EMBOJ.？2001, 20, 2424–2434.
[38]
Chernomordik, L.V.; Kozlov, M.M. Protein-lipid interplay in fusion and fission of biological membranes. Ann. Rev. Biochem.？2003, 72, 175–207.
[39]
Bigalke, H.; Shoer, L.F. Clostridial neurotoxins. In Bacterial Protein Toxins; Aktories, K., Just, I., Eds.; Springer: Berlin, Germany, 2000; pp. 407–443.
[40]
Herreros, J.; Lalli, G.; Montecucco, C.; Schiavo, G. Pathophysiological properties of clostridial neurotoxins. In The Comprehensive Sourcebook of Bacterial Protein Toxins; Alouf, J.E., Freer, J.H., Eds.; Academic Press: London, UK, 1999; Volume 2, pp. 202–228.
[41]
Humeau, Y.; Doussau, F.; Grant, N.J.; Poulain, B. How botulinum and tetanus neurotoxins block neurotransmitter. Biochimie？2000, 82, 427–446.
[42]
Meunier, F.A.; Herreros, J.; Schiavo, G.; Poulain, B.; Molgo, J. Molecular mechanism of action of botulinal neurotoxins and the synaptic remodeling they induce in vivo at the skeletal neuromuscular junction. In Handbook of Neurotoxicology; Massaro, J., Ed.; Humana Press: Totowa, NJ, USA, 2002; Volume 1, pp. 305–347.
[43]
Meunier, F.A.; Schiavo, G.; Molgo, J. Botulinum neurotoxins: From paralysis to recovery of functional neuromuscular trasnmission. J. Physiol.？2002, 96, 105–113.
[44]
Poulain, B.; Popoff, M.R.; Molgo, J. How do the botulinum neurotoxins block neurotransmitter release: From botulism to the molecular mechanism of action. Botulinum. J.？2008, 1, 14–87.
[45]
Schiavo, G.; Matteoli, M.; Montecucco, C. Neurotoxins affecting neuroexocytosis. Physiol. Rev.？2000, 80, 717–766.
Smith, T.J.; Hill, K.K.; Foley, B.T.; Detter, J.C.; Munk, A.C.; Bruce, D.C.; Doggett, N.A.; Smith, L.A.; Marks, J.D.; Xie, G.; Brettin, T.S. Analysis of the neurotoxin complex genes in clostridium botulinum A1-A4 and B1 strains: BoNT/A3, /Ba4 and /B1 clusters are located within plasmids. PLoS ONE？2007, 2, e1271.
[48]
Smith, T.J.; Lou, J.; Geren, N.; Forsyth, M.; Tsai, R.; La Porte, S.L.; Tepp, W.H.; Bradshaw, M.; Johnson, E.A.; Smith, L.A.; Marks, J.D. Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization. Infect. Immun.？2005, 73, 5450–5457.
[49]
Arndt, E.R.; Jacobson, M.J.; Abola, E.E.; Forsyth, C.M.; Tepp, W.H.; Marks, J.D.; Johnson, E.A.; Stevens, E.S. A structural perspective of the sequence variability within botulinum neurotoxin subtypes A1–A4. J. Mol. Biol.？2006, 362, 733–742.
[50]
Chen, Y.; Korkeala, H.; Aarnikunnas, J.; Lindstrom, M. Sequencing the botulinum neurotoxin gene and related genes in Clostridium botulinum type E strains reveals orfx3 and a novel type E neurotoxin subtype. J. Bacteriol.？2007, 189, 8643–8650.
[51]
Carter, A.T.; Paul, C.; Mason, D.R.; Twine, S.M.; Alston, M.J.; Logan, S.M.; Austin, J.W.; Peck, M.W. Independent evolution of neurotoxin and flagellar genetic loci in proteolytic Clostridium botulinum. BMC Genomics？2009, 10, 115.
[52]
Popoff, M.R.; Marvaud, J.C. Structural and genomic features of clostridial neurotoxins. In The Comprehensive Sourcebook of Bacterial Protein Toxins, 2nd; Alouf, J.E., Freer, J.H., Eds.; Academic Press: London, UK, 1999; Volume 2, pp. 174–201.
[53]
Hasegawa, K.; Watanabe, T.; Suzuki, T.; Yamano, A.; Oikawa, T.; Sato, Y.; Kouguchi, H.; Yoneyama, T.; Niwa, K.; Ikeda, T.; Ohyama, T. A novel subunit structure of clostridium botulinum serotype D toxin complex with three extended arms. J. Biol. Chem.？2007, 282, 24777–24783.
[54]
Lietzow, M.A.; Gielow, E.T.; Le, D.; Zhang, J.; Verhagen, M.F. Subunit stoichiometry of the Clostridium botulinum type A neurotoxin complex determined using denaturing capillary electrophoresis. Protein J.？2008, 27, 420–425.
[55]
Call, J.E.; Cooke, P.H.; Miller, A.J. In situ characterization of Clostridium botulinum neurotoxin synthesis and export. J. Appl. Bacteriol.？1995, 79, 257–263.
[56]
Emsley, P.; Fotinou, C.; Black, I.; Fairweather, N.F.; Charles, I.G.; Watts, C.; Hewitt, E.; Isaacks, N.W. The structures of the Hc fragment of Tetanus Toxin with carbohydrate subunit complexes provide insight into ganglioside binding. J. Biol. Chem.？2000, 275, 8889–8894.
[57]
Lacy, D.B.; Stevens, R.C. Sequence homology and structural analysis of the clostridial neurotoxins. J. Mol. Biol.？1999, 291, 1091–1104.
[58]
Lacy, D.B.; Tepp, W.; Cohen, A.C.; Das Gupta, B.R.; Stevens, R.C. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat. Struct. Biol.？1998, 5, 898–902.
[59]
Umland, T.C.; Wingert, L.M.; Swaminathan, S.; Furey, W.F.; Schmidt, J.J.; Sax, M. The structure of the receptor binding fragment Hc of tetanus neurotoxin. Nat. Struct. Biol.？1997, 4, 788–792.
[60]
Fotinou, C.; Emsley, P.; Black, I.; Ando, H.; Ishida, H.; Kiso, M.; Sinha, K.A.; Fairweather, N.F.; Isaacs, N.W. The crystal structure of Tetanus toxin Hc fragment complexed with a synthetic GT1b analogue suggests cross-linking between ganglioside receptors and the toxin. J. Biol. Chem.？2001, 276, 3274–3281.
[61]
Breidenbach, M.A.; Brunger, A.T. 2.3 A crystal structure of tetanus neurotoxin light chain. Biochemistry？2005, 44, 7450–7457.
[62]
Fu, Z.; Chen, S.; Baldwin, M.R.; Boldt, G.E.; Crawford, A.; Janda, K.D.; Barbieri, J.T.; Kim, J.J. Light chain of botulinum neurotoxin serotype A: Structural resolution of a catalytic intermediate. Biochemistry？2006, 45, 8903–8911.
[63]
Swaminathan, S.; Eswaramoorthy, S. Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat. Struct. Biol.？2000, 7, 693–699.
[64]
Stenmark, P.; Dupuy, J.; Imamura, A.; Kiso, M.; Stevens, R.C. Crystal structure of botulinum neurotoxin type A in complex with the cell surface co-receptor GT1b-insight into the toxin-neuron interaction. PLoS Pathogen？2008, 4, e1000129.
[65]
Kumaran, D.; Eswaramoorthy, S.; Furey, W.; Navaza, J.; Sax, M.; Swaminathan, S. Domain organization in Clostridium botulinum neurotoxin type E is unique: Its implication in faster translocation. J. Mol. Biol.？2009, 386, 233–245.
[66]
Maksymowych, A.B.; Simpson, L.L. Binding and transcytosis of botulinum neurotoxin by polarized human carcinoma cells. J. Biol. Chem.？1998, 273, 21950–21957.
[67]
Maksymowych, A.B.; Simpson, L.I. Structural features of the botulinum neurotoxin molecule that govern binding and transcytosis across polarized human intestinal epithelial cells. J. Pharmacol. Exp. Ther.？2004, 210, 633–641.
[68]
Ahsan, C.R.; Hajnoczky, G.; Maksymowych, A.B.; Simpson, L.L. Visualization of binding and transcytosis of botulinum toxin by human intestinal epithelial cells. J. Pharmacol. Exp. Ther.？2005, 315, 1028–1035.
[69]
Couesnon, A.; Pereira, Y.; Popoff, M.R. Receptor-mediated transcytosis of botulinum neurotoxin A through intestinal cell monolayers. Cell Microbiol.？2008, 10, 375–387. 17900298
[70]
Matsumura, T.; Jin, Y.; Kabumoto, Y.; Takegahara, Y.; Oguma, K.; Lencer, W.I.; Fujinaga, Y. The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorption. Cel Microbiol.？2007, 10, 355–364.
[71]
Jin, Y.; Takegahara, Y.; Sugawara, Y.; Matsumura, T.; Fujinaga, Y. Disruption of the epithelial barrier by botulinum haemagglutinin (HA) proteins—differences in cell tropism and the mechanism of action between HA proteins of types A or B, and HA proteins of type C. Microbiology？2009, 155, 35–45.
[72]
Wellh？ner, H.H. Clostridial toxins and the central nervous system: Studies on in situ tissues. In Botulinum Neurotoxin and Tetanus Toxin; Simpson, L.L., Ed.; Academic Press: San Diego, CA, USA, 1989; pp. 231–253.
[73]
Manning, K.A.; Erichsen, J.T.; Evinger, C. Retrograde transneuronal transport properties of fragment C of tetanus toxin. Neuroscience？1990, 34, 251–263.
[74]
Rossetto, O.; Seveso, M.; Caccin, P.; Schiavo, G.; Montecucco, C. Tetanus and botulinum neurotoxins: Turning bad guys into good by research. Toxicon？2001, 39, 27–41.
[75]
Dong, M.; Liu, H.; Tepp, W.H.; Johnson, E.A.; Janz, R.; Chapman, E.R. Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol. Biol. Cell.？2008, 19, 522–637.
[76]
Dong, M.; Tepp, W.H.; Liu, H.; Johnson, E.A.; Chapman, E.R. Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons. J. Cell. Biol.？2007, 179, 1511–1522.
[77]
Dong, M.; Yeh, F.; Tepp, W.H.; Dean, C.; Johnson, E.A.; Janz, R.; Chapman, E.R. SV2 is the protein receptor for botulinum neurotoxin A. Science？2006, 312, 592–596.
[78]
Mahrhold, S.; Rummel, A.; Bigalke, H.; Davletov, B.; Binz, T. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett.？2006, 580, 2011–2014.
[79]
Nishiki, T.; Kamata, Y.; Nemoto, Y.; Omori, A.; Ito, T.; Takahashi, M.; Kozaki, S. Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J. Biol. Chem.？1994, 269, 10498–10503.
[80]
Rummel, A.; Hafner, K.; Mahrhold, S.; Darashchonak, N.; Holt, M.; Jahn, R.; Beermann, S.; Karnath, T.; Bigalke, H.; Binz, T. 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.？2009, 110, 1942–1954.
[81]
Rummel, A.; Karnath, T.; Henke, T.; Bigalke, H.; Binz, T. Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. J. Biol. Chem.？2004, 279, 30865–30870.
[82]
Herreros, J.; Ng, T.; Schiavo, G. Lipid rafts act as specialized domains for tetanus toxin binding and internalization into neurons. Mol. Biol. Cell？2001, 12, 2947–2960.
[83]
Munro, P.; Kojima, H.; Dupont, J.L.; Bossu, J.L.; Poulain, B.; Boquet, P. High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein. Biochem. Biophys. Res. Comm.？2001, 289, 623–629.
[84]
Rummel, A.; Bade, S.; Alves, J.; Bigalke, H.; Binz, T. Two carbohydrate binding sites in the Hcc-domain of tetanus neurotoxin are required for toxicity. J. Mol. Biol.？2003, 326, 835–847.
[85]
Rummel, A.; Eichner, T.; Weil, T.; Karnath, T.; Gutcaits, A.; Mahrhold, S.; Sandhoff, K.; Proia, R.L.; Acharya, K.R.; Bigalke, H.; Binz, T. Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept. Proc. Natl. Acad. Sci. USA？2007, 104, 359–364.
[86]
Rummel, A.; Mahrhold, S.; Bigalke, H.; Binz, T. The Hcc-domain of botulinum neurotoxins A and B exhibits a singular gangliosside binding site displaying serotype specific carbohydrate interaction. Mol. Microbiol.？2004, 51, 631–643.
[87]
Chen, C.; Fu, Z.; Kim, J.J.; Barbieri, J.T.; Baldwin, M.R. Gangliosides as high affinity receptors for tetanus neurotoxin. J. Biol. Chem.？2009, 284, 26569–26577.
[88]
Tsukamoto, K.; Kozai, Y.; Ihara, H.; Kohda, T.; Mukamoto, M.; Tsuji, T.; Kozaki, S. Identification of the receptor-binding sites in the carboxyl-terminal half of the heavy chain of botulinum neurotoxin types C and D. Microb. Pathog.？2008, 44, 484–493.
[89]
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. Commun.？2009, 380, 76–80.
[90]
Yowler, B.C.; Schengrund, C.L. Botulinum neurotoxin A changes conformation upon binding to ganglioside GT1b. Biochemistry？2004, 43, 9725–9731.
Burgen, A.S.; Dickens, F.; Zatman, L.J. The action of botulinum toxin on the neuro-muscular junction. J. Physiol.？1949, 109, 10–24.
[93]
Dunant, Y.; Esquerda, J.E.; Loctin, F.; Marsal, J.; Muller, D. Botulinum toxin inhibits quantal acetylcholine release and energy metabolism in the Torpedo electric organ. J. Physiol.？1987, 385, 677–692.
[94]
Poulain, B.; Tauc, L.; Maisey, E.A.; Wadsworth, J.D.; Mohan, P.M.; Dolly, J.O. 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. USA？1988, 85, 4090–4094.
[95]
Sanchez-Prieto, J.; Sihra, T.S.; Evans, D.; Ashton, A.; Dolly, J.O.; Nicholls, D.G. Botulinum toxin A blocks glutamate exocytosis from guinea-pig cerebral cortical synaptosomes. Eur. J. Biochem.？1987, 165, 675–681.
[96]
Cui, M.; Khanijou, S.; Rubino, J.; Aoki, K.R. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain？2004, 107, 125–133.
[97]
Foran, P.G.; Mohammed, N.; Lisk, G.O.; Nagwaney, S.; Lawrence, G.W.; Johnson, E.; Smith, L.; Aoki, K.R.; Dolly, O.J. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E and F compared with the long lasting type A. J. Biol. Chem.？2003, 278, 1363–1371.
[98]
Khairallah, G.; Andreoletti, J.B.; Jover, E.; Simon, E. Measurement of botulinum toxin activity: Towards a new cellular culture assay? Ann. Chir. Plast. Esthet.？2008, 53, 42–49.
[99]
McMahon, H.T.; Foran, P.; Dolly, J.O.; Verhage, M.; Wiegant, V.M.; Nicholls, D.G. 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.？1992, 267, 21338–21343. 1356988
[100]
Ashton, A.C.; Dolly, J.O. Characterization of the inhibitory action of botulinum neurotoxin type A on the release of several transmitters from rat cerebrocortical synaptosomes. J. Neurochem.？1988, 50, 1808–1816.
[101]
Neale, E.A.; Bowers, L.M.; Jia, M.; Bateman, K.E.; Williamson, L.C. Botulinum neurotoxin A blocks synaptic vesicle exocytosis but not endocytosis at the nerve terminal. J. Cell. Biol.？1999, 147, 1249–1260.
[102]
Maisey, E.A.; Wadsworth, J.D.; Poulain, B.; Shone, C.C.; Melling, J.; Gibbs, P.; Tauc, L.; Dolly, J.O. Involvement of the constituent chains of botulinum neurotoxins A and B in the blockade of neurotransmitter release. Eur. J. Biochem.？1988, 177, 683–691.
[103]
Najib, A.; Pelliccioni, P.; Gil, C.; Aguilera, J. Clostridium neurotoxins influence serotonin uptake and release differently in rat brain synaptosomes. J. Neurochem.？1999, 72, 1991–1998.
[104]
Marsal, J.; Egea, G.; Solsona, C.; Rabasseda, X.; Blasi, J. Botulinum toxin type A blocks the morphological changes induced by chemical stimulation on the presynaptic membrane of Torpedo synaptosomes. Proc. Natl. Acad. Sci. USA？1989, 86, 372–376.
[105]
Khera, M.; Somogyi, G.T.; Kiss, S.; Boone, T.B.; Smith, C.P. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem. Int.？2004, 45, 987–993.
[106]
Smith, C.P.; Vemulakonda, V.M.; Kiss, S.; Boone, T.B.; Somogyi, G.T. Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: Effect of botulinum toxin A. Neurochem. Int.？2005, 47, 291–297.
[107]
Tompkins, J.D.; Parsons, R.L. Exocytotic release of ATP and activation of P2X receptors in dissociated guinea pig stellate neurons. Am. J. Physiol. Cell Physiol.？2006, 291, C1062–C1071.
[108]
Smyth, L.M.; Breen, L.T.; Mutafova-Yambolieva, V.N. Nicotinamide adenine dinucleotide is released from sympathetic nerve terminals via a botulinum neurotoxin A-mediated mechanism in canine mesenteric artery. Am. J. Physiol. Heart. Circ. Physiol.？2006, 290, H1818–H1825.
[109]
Breen, L.T.; Smyth, L.M.; Yamboliev, I.A.; Mutafova-Yambolieva, V.N. beta-NAD is a novel nucleotide released on stimulation of nerve terminals in human urinary bladder detrusor muscle. Am. J. Physiol. Renal. Physiol.？2006, 290, F486–F495.
[110]
Welch, M.J.; Purkiss, J.R.; Foster, K.A. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon？2000, 38, 245–258.
[111]
Duggan, M.J.; Quinn, C.P.; Chaddock, J.A.; Purkiss, J.R.; Alexander, F.C.; Doward, S.; Fooks, S.J.; Friis, L.M.; Hall, Y.H.; Kirby, E.R.; Leeds, N.; Moulsdale, H.J.; Dickenson, A.; Green, G.M.; Rahman, W.; Suzuki, R.; Shone, C.C.; Foster, K.A. Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. J. Biol. Chem.？2002, 277, 34846–34852.
[112]
Durham, P.L.; Cady, R.; Cady, R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: Implications for migraine therapy. Headache: J. Head and Face Pain？2004, 44, 35–42, doi:10.1111/j.1526-4610.2004.04007.x.
[113]
Rapp, D.E.; Turk, K.W.; Bales, G.T.; Cook, S.P. Botulinum toxin type an inhibits calcitonin gene-related peptide release from isolated rat bladder. J. Urol.？2006, 175, 1138–1142.
[114]
Hassan, S.M.; Jennekens, F.G.; Wieneke, G.; Veldman, H. Calcitonin gene-related peptide-like immunoreactivity, in botulinum toxin-paralysed rat muscles. Neuromuscul. Disord.？1994, 4, 489–496.
[115]
Meunier, F.A.; Colasante, C.; Faille, L.; Gastard, M.; Molgo, J. Upregulation of calcitonin gene-related peptide at mouse motor nerve terminals poisoned with botulinum type-A toxin. Pflugers. Arch.？1996, 431(Suppl. 2), R297–R298.
[116]
Sala, C.; Andreose, J.S.; Fumagalli, G.; Lomo, T. Calcitonin gene-related peptide: Possible role in formation and maintenance of neuromuscular junctions. J. Neurosci.？1995, 15, 520–528.
[117]
Tarabal, O.; Caldero, J.; Ribera, J.; Sorribas, A.; Lopez, R.; Molgo, J.; Esquerda, J.E. Regulation of motoneuronal calcitonin gene-related peptide (CGRP) during axonal growth and neuromuscular synaptic plasticity induced by botulinum toxin in rats. Eur. J. Neurosci.？1996, 8, 829–836.
[118]
Swartling, C.; Naver, H.; Pihl-Lundin, I.; Hagforsen, E.; Vahlquist, A. Sweat gland morphology and periglandular innervation in essential palmar hyperhidrosis before and after treatment with intradermal botulinum toxin. J. Am. Acad. Dermatol.？2004, 51, 739–745.
[119]
Morris, J.L.; Jobling, P.; Gibbins, I.L. Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons. Am. J. Physiol. Heart. Circ. Physiol.？2002, 283, H2627–H2635.
[120]
Jones, O.M.; Brading, A.F.; Mortensen, N.J. Mechanism of action of botulinum toxin on the internal anal sphincter. Br. J. Surg.？2004, 91, 224–228.
[121]
Moffatt, J.D.; Cocks, T.M.; Page, C.P. Role of the epithelium and acetylcholine in mediating the contraction to 5-hydroxytryptamine in the mouse isolated trachea. Br. J. Pharmacol.？2004, 141, 1159–1166.
[122]
Verderio, C.; Pozzi, D.; Pravettoni, E.; Inverardi, F.; Schenk, U.; Coco, S.; Proux-Gillardeaux, V.; Galli, T.; Rossetto, O.; Frassoni, C.; Matteoli, M. SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization. Neuron？2004, 41, 599–610.
[123]
Penner, R.; Neher, E.; Dreyer, F. Intracellularly injected tetanus toxin inhibits exocytosis in bovine adrenal chromaffin cells. Nature？1986, 324, 76–78.
[124]
Ahnert-Hilger, G.; Bader, M.F.; Bhakdi, S.; Gratzl, M. Introduction of macromolecules into bovine adrenal medullary chromaffin cells and rat pheochromocytoma cells (PC12) by permeabilization with streptolysin O: Inhibitory effect of tetanus toxin on catecholamine secretion. J. Neurochem.？1989, 52, 1751–1758.
Abdipranoto, A.; Liu, G.J.; Werry, E.L.; Bennett, M.R. Mechanisms of secretion of ATP from cortical astrocytes triggered by uridine triphosphate. Neuroreport？2003, 14, 2177–2181.
[127]
Araque, A.; Li, N.; Doyle, R.T.; Haydon, P.G. SNARE protein-dependent glutamate release from astrocytes. J. Neurosci.？2000, 20, 666–673.
[128]
Verderio, C.; Coco, S.; Rossetto, O.; Montecucco, C.; Matteoli, M. Internalization and proteolytic action of botulinum toxins in CNS neurons and astrocytes. J. Neurochem.？1999, 73, 372–379.
Rosado, J.A.; Redondo, P.C.; Salido, G.M.; Sage, S.O.; Pariente, J.A. Cleavage of SNAP-25 and VAMP-2 impairs store-operated Ca2+ entry in mouse pancreatic acinar cells. Am. J. Physiol. Cell. Physiol.？2005, 288, C214–C221.
[131]
Redondo, P.C.; Harper, A.G.; Salido, G.M.; Pariente, J.A.; Sage, S.O.; Rosado, J.A. A role for SNAP-25 but not VAMPs in store-mediated Ca2+ entry in human platelets. J. Physiol.？2004, 558, 99–109.
[132]
Semba, T.; Kano, M. Glycine in the spinal cord of cats with local tetanus rigidity. Science？1969, 164, 571–572.
[133]
Fedinec, A.A.; Shank, R.P. Effect of tetanus toxin on the content of glycine, gamma-aminobutyric acid, glutamate, glutamine and aspartate in the rat spinal cord. J. Neurochem.？1971, 18, 2229–2234.
[134]
Williamson, L.C.; Fitzgerald, S.C.; Neale, E.A. Differential effects of tetanus toxin on inhibitory and excitatory neurotransmitter release from mammalian spinal cord cells in culture. J. Neurochem.？1992, 59, 2148–2157.
[135]
Habermann, E. Inhibition by tetanus and botulinum A toxin of the release of [3H]noradrenaline and [3H]GABA from rat brain homogenate. Experientia？1988, 44, 224–226.
[136]
Collingridge, G.L.; Davies, J. Reversible effects of tetanus toxin on striatal-evoked responses and [3H]-gamma-aminobutyric acid release in the rat substantia nigra. Br. J. Pharmacol.？1982, 76, 403–411.
[137]
Collingridge, G.L.; Thompson, P.A.; Davies, J.; Mellanby, J. In vitro effect of tetanus toxin on GABA release form rat hippocampal slices. J. Neurochem.？1981, 37, 1039–1041.
[138]
Albus, U.; Habermann, E. Tetanus toxin inhibits the evoked outflow of an inhibitory (GABA) and an excitatory (D-aspartate) amino acid from particulate brain cortex. Toxicon？1983, 21, 97–110.
[139]
Pearce, B.R.; Gard, A.L.; Dutton, G.R. Tetanus toxin inhibition of K+-stimulated [3H]GABA release from developing cell cultures of the rat cerebellum. J. Neurochem.？1983, 40, 887–890.
[140]
Van Vliet, B.J.; Sebben, M.; Dumuis, A.; Gabrion, J.; Bockaert, J.; Pin, J.P. Endogenous amino acid release from cultured cerebellar neuronal cells: effect of tetanus toxin on glutamate release. J. Neurochem.？1989, 52, 1229–1239.
[141]
Bagetta, G.; Nistico, G. Glutamate transmission is involved in the mechanisms of neuronal degeneration produced by intrahippocampal tetanus toxin in rats. Toxicol. Lett.？1992, 64-65, 447–453, doi:10.1016/0378-4274(92)90218-9. 1361694
[142]
Bradford, S.E.; Nadler, J.V. Aspartate release from rat hippocampal synaptosomes. Neuroscience？2004, 128, 751–765.
[143]
Lu, W.; Man, H.; Ju, W.; Trimble, W.S.; MacDonald, J.F.; Wang, Y.T. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron？2001, 29, 243–254.
[144]
Lindlbauer, R.; Mohrmann, R.; Hatt, H.; Gottmann, K. Regulation of kinetic and pharmacological properties of synaptic NMDA receptors depends on presynaptic exocytosis in rat hippocampal neurones. J. Physiol.？1998, 508, 495–502.
[145]
Fleck, M.W.; Barrionuevo, G.; Palmer, A.M. Release of D, L-threo-beta-hydroxyaspartate as a false transmitter from excitatory amino acid-releasing nerve terminals. Neurochem. Int.？2001, 39, 75–81.
[146]
Habermann, E.; Muller, H.; Hudel, M. Tetanus toxin and botulinum A and C neurotoxins inhibit noradrenaline release from cultured mouse brain. J. Neurochem.？1988, 51, 522–527.
[147]
Figliomeni, B.; Grasso, A. Tetanus toxin affects the K+-stimulated release of catecholamines from nerve growth factor-treated PC12 cells. Biochem. Biophys. Res. Commun.？1985, 128, 249–256.
[148]
Bansal, M.K.; Phillips, J.H.; van Heyningen, S. The inhibition by pertussis and tetanus toxins of evoked catecholamine release from intact and permeabilized bovine adrenal chromaffin cells. FEBS Lett.？1990, 276, 165–168.
[149]
Stecher, B.; Hens, J.; Weller, U.; Gratzl, M.; Gispen, W.H.; De Graan, P.N. Noradrenaline release from permeabilized synaptosomes is inhibited by the light chain of tetanus toxin. FEBS Lett.？1992, 312, 192–194.
[150]
Ashton, A.C.; Dolly, J.O. Microtubules and microfilaments participate in the inhibition of synaptosomal noradrenaline release by tetanus toxin. J. Neurochem.？1997, 68, 649–658.
[151]
Tuz, K.; Pasantes-Morales, H. Hyposmolarity evokes norepinephrine efflux from synaptosomes by a depolarization- and Ca2+-dependent exocytotic mechanism. Eur. J. Neurosci.？2005, 22, 1636–1642.
[152]
Britton, P.; Whitton, P.S.; Bowery, N.G. Effect of tetanus toxin on basal and evoked release of 5-hydroxytryptamine and dopamine in rat hippocampus in vivo. Brain Res.？1995, 673, 331–334.
[153]
Whitton, P.S.; Britton, P.; Bowery, N.G. Tetanus toxin alters 5-hydroxytryptamine, dopamine, and their metabolites in rat hippocampus measured by in vivo microdialysis. Neurosci. Lett.？1992, 144, 95–98.
[154]
Gobbi, M.; Facchiano, F.; Frittoli, E.; Luini, A.; Mennini, T. Tetanus toxin inhibits depolarization-induced [3H]serotonin release from rat brain cortex synaptosomes. Neurosci. Lett.？1993, 151, 205–208.
[155]
Inserte, J.; Najib, A.; Pelliccioni, P.; Gil, C.; Aguilera, J. Inhibition by tetanus toxin of sodium-dependent, high-affinity [3H]5-hydroxytryptamine uptake in rat synaptosomes. Biochem. Pharmacol.？1999, 57, 111–120.
[156]
Gil, C.; Najib, A.; Aguilera, J. Serotonin transport is modulated differently by tetanus toxin and growth factors. Neurochem. Int.？2003, 42, 535–542.
[157]
Pelliccioni, P.; Gil, C.; Najib, A.; Sarri, E.; Picatoste, F.; Aguilera, J. Tetanus toxin modulates serotonin transport in rat-brain neuronal cultures. J. Mol. Neurosci.？2001, 17, 303–310.
[158]
Najib, A.; Pelliccioni, P.; Gil, C.; Aguilera, J. Serotonin transporter phosphorylation modulated by tetanus toxin. FEBS Lett.？2000, 486, 136–142.
[159]
Sandberg, K.; Berry, C.J.; Eugster, E.; Rogers, T.B. A role for cGMP during tetanus toxin blockade of acetylcholine release in the rat pheochromocytoma (PC12) cell line. J. Neurosci.？1989, 9, 3946–3954.
[160]
Sandberg, K.; Berry, C.J.; Rogers, T.B. Studies on the intoxication pathway of tetanus toxin in the rat pheochromocytoma (PC12) cell line. Binding, internalization, and inhibition of acetylcholine release. J. Biol. Chem.？1989, 264, 5679–5686. 2925628
[161]
Egea, G.; Rabasseda, X.; Solsona, C.; Marsal, J.; Bizzini, B. Tetanus toxin blocks potassium-induced transmitter release and rearrangement of intramembrane particles at pure cholinergic synaptosomes. Toxicon？1990, 28, 311–318.
[162]
Bigalke, H.; Dimpfel, W.; Habermann, E. Suppression of 3H-acetylcholine release from primary nerve cell cultures by tetanus and botulinum-A toxin. Naunyn. Schmiedebergs. Arch. Pharmacol.？1978, 303, 133–138.
[163]
Mochida, S.; Poulain, B.; Weller, U.; Habermann, E.; Tauc, L. Light chain of tetanus toxin intracellularly inhibits acetylcholine release at neuro-neuronal synapses, and its internalization is mediated by heavy chain. FEBS Lett.？1989, 253, 47–51.
[164]
Kang, N.; Xu, J.; Xu, Q.; Nedergaard, M.; Kang, J. Astrocytic glutamate release-induced transient depolarization and epileptiform discharges in hippocampal CA1 pyramidal neurons. J. Neurophysiol.？2005, 94, 4121–4130.
[165]
Galli, T.; Chilcote, T.; Mundigl, O.; Binz, T.; Niemann, H.; De Camilli, P. Tetanus toxin-mediated cleavage of cellubrevin impairs exocytosis of transferrin receptor-containing vesicles in CHO cells. J. Cell. Biol.？1994, 125, 1015–1024.
[166]
Lalli, G.; Bohnert, S.; Deinhardt, K.; Verastegui, C.; Schiavo, G. The journey of tetanus and botulinum neurotoxins in neurons. Trends Microbiol.？2003, 11, 431–437.
[167]
Lalli, G.; Schiavo, G. Analysis of retrograde transport in motor neurons reveals common endocytic carriers for tetanus toxin and neutrophin receptor p75NTR. J. Cell Biol.？2002, 156, 233–239.
[168]
Bohnert, S.; Deinhardt, K.; Salinas, S.; Schiavo, G. Uptake and transport of clostridium neurotoxins. In The Sourcebook of Comprehensive Bacterial Protein Toxins, 3rd; Alouf, J.E., Popoff, M.R., Eds.; Elsevier Academic Press: Amsterdam, The Netherland, 2006; pp. 390–408.
[169]
Bohnert, S.; Schiavo, G. Tetanus toxin is transported in a novel neuronal compartment characterized by a specialized pH regulation. J. Biol. Chem.？2005, 280, 42336–42344.
[170]
Deinhardt, K.; Berminghausen, O.; Willison, H.J.; Hopkins, C.R.; Schiavo, G. Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1. J. Cell. Biol.？2006, 174, 459–471.
[171]
Deinhardt, K.; Salinas, S.; Verastegui, C.; Watson, R.; Worth, D.; Hanrahan, S.; Bucci, C.; Schiavo, G. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron？2006, 52, 293–305.
[172]
Li, Y.; Foran, P.; Lawrence, G.; Mohammed, N.; Chan-Kwo-Chion, C.; Lisk, G.; Aoki, R.; Dolly, O. Recombinant forms of tetanus toxin engineered for examining and exploiting neuronal trafficking pathways. J. Biol. Chem.？2001, 276, 31394–31401.
[173]
Maskos, U.; Kissa, K.; St Cloment, C.; Brulet, P. Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice. Proc. Natl. Acad.Sci. USA？2002, 99, 10120–10125.
[174]
Galloux, M.; Vitrac, H.; Montagner, C.; Raffestin, S.; Popoff, M.R.; Chenal, A.; Forge, V.; Gillet, D. Membrane Interaction of botulinum neurotoxin A translocation (T) domain. The belt region is a regulatory loop for membrane interaction. J. Biol. Chem.？2008, 283, 27668–27676. 18693250
[175]
Koriazova, L.K.; Montal, M. Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Nat. Struct. Biol.？2003, 10, 13–18.
[176]
Fischer, A.; Montal, M. Crucial role of the disulfide bridge between botulinum neurotoxin light and heavy chains in protease translocation across membranes. J. Biol. Chem.？2007, 282, 29604–29611.
[177]
Montal, M. Translocation of botulinum neurotoxin light chain protease by the heavy chain protein-conducting channel. Toxicon？2009, 9, 565–569, doi:10.1016/j.toxicon.2008.11.018.
[178]
Ratts, R.; Trujillo, C.; Bharti, A.; vanderSpek, J.; Harrison, R.; Murphy, J.R. A conserved motif in transmembrane helix 1 of diphtheria toxin mediates catalytic domain delivery to the cytosol. Proc. Natl. Acad. Sci. USA？2005, 102, 15635–15640.
[179]
Tucker, W.C.; Weber, T.; Chapman, E.R. Reconstitution of Ca2+-regulated membrane fusion by synaptotagmin and SNAREs. Science？2004, 304, 435–438.
[180]
Sakaba, T.; Stein, A.; Jahn, R.; Neher, E. Distinct kinetic changes in neurotransmitter release after SNARE protein cleavage. Science？2005, 309, 491–494.
Gerona, R.R.; Larsen, E.C.; Kowalchyk, J.A.; Martin, T.F. The C terminus of SNAP25 is essential for Ca(2+)-dependent binding of synaptotagmin to SNARE complexes. J. Biol. Chem.？2000, 275, 6328–6336.
[183]
Apland, J.P.; Adler, M.; Oyler, G.A. Inhibition of neurotransmitter release by peptides that mimic the N-terminal domain of SNAP-25. J. Protein. Chem.？2003, 22, 147–153.
[184]
Gutierrez, R.; Garcia, T.; Gonzalez, I.; Sanz, B.; Hernandez, P.E.; Martin, R. A quantitative PCR-ELISA for the rapid enumeration of bacteria in refrigerated raw milk. J. Appl. MIcrobiol.？1997, 83, 518–523.
[185]
Keller, J.E.; Neale, E.A. The role of the synaptic protein snap-25 in the potency of botulinum neurotoxin type A. J. Biol. Chem.？2001, 276, 13476–13482.
[186]
Chen, Y.A.; Scales, S.J.; Jagath, J.R.; Scheller, R.H. A discontinuous SNAP-25 C-terminal coil supports exocytosis. J. Biol. Chem.？2001, 276, 28503–28508.
[187]
Chen, Y.A.; Scales, S.J.; Patel, S.M.; Doung, Y.C.; Scheller, R.H. SNARE complex formation is triggered by Ca2+ and drives membrane fusion. Cell？1999, 97, 165–174.
[188]
Schuette, C.G.; Hatsuzawa, K.; Margittai, M.; Stein, A.; Riedel, D.; Kuster, P.; Konig, M.; Seidel, C.; Jahn, R. Determinants of liposome fusion mediated by synaptic SNARE proteins. Proc. Natl. Acad. Sci. USA？2004, 101, 2858–2863.
[189]
Bajohrs, M.; Rickman, C.; Binz, T.; Davletov, B. A molecular basis underlying differences in the toxicity of botulinum serotypes A and E. EMBO Rep.？2004, 5, 1090–1095.
[190]
Salem, N.; Faundez, V.; Horng, J.T.; Kelly, R.B. A v-SNARE participates in synaptic vesicle formation mediated by the AP3 adaptor complex. Nat. Neurosci.？1998, 1, 551–556.
[191]
Cornille, F.; Deloye, F.; Fournie-Zaluski, M.C.; Roques, B.P.; Poulain, B. Inhibition of neurotransmitter release by synthetic proline-rich peptides shows that the N-terminal domain of vesicle-associated membrane protein/synaptobrvin is critical for neuro-exocytosis. J. Biol. Chem.？1995, 270, 16826–16832.
[192]
Foran, P.; Lawrence, G.W.; Shone, C.C.; Foster, K.A.; Dolly, J.O. Botulinum neurotoxin C1 cleaves both syntaxin and SNAP-25 in intact and permeabilized chro-maffin cells: Correlation with its blockade of catecholamine release. Biochemistry？1996, 35, 2630–2636.
[193]
Vaidyanathan, V.V.; Yoshino, K.; Jahnz, M.; Dorries, C.; Bade, S.; Nauenburg, S.; Niemann, H.; Binz, T. Proteolysis of SNAP-25 isoforms by botulinum neurotoxin types A, C, and E: Domains and amino acid residues controlling the formation of enzyme-substrate complexes and cleavage. J. Neurochem.？1999, 72, 327–337.
[194]
O'Connor, V.; Heuss, C.; De Bello, W.M.; Dresbach, T.; Charlton, M.P.; Hunt, J.H.; Pellegrini, L.L.; Hodel, A.; Burger, M.M.; Betz, H.; Augustine, G.J.; Schafer, T. Disruption of syntaxin-mediated protein interactions blocks neurotransmitter secretion. Proc. Natl. Acad. Sci. USA？1997, 94, 12186–12191.
[195]
Capogna, M.; McKinney, R.A.; O'Connor, V.; Gahwiler, B.H.; Thompson, S.M. Ca2+ or Sr2+ partially rescues synaptic transmission in hippocampal cultures treated with botulinum toxin A and C, but not tetanus toxin. J. Neurosci.？1997, 17, 7190–7202.
[196]
Williamson, L.C.; Halpern, J.L.; Montecucco, C.; Brown, J.E.; Neale, E.A. Clostridial neurotoxins and substrate proteolysis in intact neurons: Botulinum neurotoxin C acts on synaptosomal-associated protein of 25 kDa. J. Biol. Chem.？1996, 271, 7694–7699.
[197]
Poulain, B.; Stiles, B.G.; Popoff, M.R.; Molgo, J. Attack of the nervous system by clostridial toxins: Physical findings, cellular and molecular actions. In The Sourcebook of Bacterial Protein Toxins, 3rd; Alouf, J.E., Popoff, M.R., Eds.; Elsevier Academic Press: Amsterdam, The Netherland, 2006; pp. 348–389.
[198]
Keller, J.E.; Neale, E.A.; Oyler, G.; Adler, M. Persistence of botulinum neurotoxin action in cultured spinal cord cells. FEBS Lett.？1999, 456, 137–142.
[199]
O'Sullivan, G.A.; Mohammed, N.; Foran, P.G.; Lawrence, G.W.; Dolly, J.O. Rescue of exocytosis in botulinum toxin A-poisoned chromaffin cells by expression of cleavage-resistant SNAP-25. J. Biol. Chem.？1999, 274, 36897–36904.
[200]
Fernandez-Salas, E.; Steward, L.E.; Ho, H.; Garay, P.E.; Sun, S.W.; Gilmore, M.A.; Ordas, J.V.; Wang, J.; Francis, J.; Aoki, K.R. Plasma membrane localization signals in the light chain of botulinum neurotoxin. Proc. Natl. Acad. Sci. USA？2004, 101, 3208–3213.
[201]
Hayashi, T.; McMahon, H.; Yamashi, S.; Binz, T.; Hata, Y.; Südhof, T.C.; Niemann, H. Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO J.？1994, 13, 5051–5061.
[202]
Pellegrini, L.L.; O'Connor, V.; Lottspeich, F.; Betz, H. Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion. EMBO J.？1995, 14, 4705–4713.
[203]
Cohen, R.; Atlas, D. R-type voltage-gated Ca(2+) channel interacts with synaptic proteins and recruits synaptotagmin to the plasma membrane of Xenopus oocytes. Neuroscience？2004, 128, 831–841.
[204]
Degtiar, V.E.; Scheller, R.H.; Tsien, R.W. Syntaxin modulation of slow inactivation of N-type calcium channels. J. Neurochem.？2000, 20, 4355–4367.
[205]
Stanley, E.F. Syntaxin I modulation of presynaptic calcium channel inactivation revealed by botulinum toxin C1. Eur. J. Neurosci.？2003, 17, 1303–1305.
[206]
Wiser, O.; Trus, M.; Hernandez, A.; Renstrom, E.; Barg, S.; Rorsman, P.; Atlas, D. The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc. Natl. Acad. Sci. USA？1999, 96, 248–253.
[207]
Bergsman, J.B.; Tsien, R.W. Syntaxin modulation of calcium channels in cortical synaptosomes as revealed by botulinum toxin C1. J. Neurosci.？2000, 20, 4368–4378.
[208]
Aleu, J.; Blasi, J.; Solsona, C.; Marsal, J. Calcium-dependent acetylcholine release from Xenopus oocytes: Simultaneous ionic currents and acetylcholine release recordings. Eur. J. Neurochem.？2002, 8, 1442–1448.
[209]
Stanley, E.F.; Mirotznik, R.R. Cleavage of syntaxin prevents G-protein regulation of presynaptic calcium channels. Nature？1997, 385, 340–343.
[210]
Ji, J.; Tsuk, S.; Salapatek, A.M.; Huang, X.; Chikvashvili, D.; Pasyk, E.A.; Kang, Y.; Sheu, L.; Tsushima, R.; Diamant, N.; Trimble, W.S.; Lotan, I.; Gaisano, H.Y. The 25-kDa synaptosome-associated protein (SNAP-25) binds and inhibits delayed rectifier potassium channels in secretory cells. J. Biol. Chem.？2002, 277, 20195–20204.
[211]
Putney, J.W., Jr. A model for receptor-regulated calcium entry. Cell Calcium？1986, 7, 1–12.
[212]
Lewis, R.S. The molecular choreography of a store-operated calcium channel. Nature？2007, 446, 284–287.
[213]
Yao, Y.; Ferrer-Montiel, A.V.; Montal, M.; Tsien, R.Y. Activation of store-operated Ca2+ current in Xenopus oocytes requires SNAP-25 but not a diffusible messenger. Cell？1999, 98, 475–485.
[214]
Alderton, J.M.; Ahmed, S.A.; Smith, L.A.; Steinhardt, R.A. Evidence for a vesicle-mediated maintenance of store-operated calcium channels in a human embryonic kidney cell line. Cell Calcium？2000, 28, 161–169.
[215]
Rosado, J.A.; Redondo, P.C.; Sage, S.O.; Pariente, J.A.; Salido, G.M. Store-operated Ca2+ entry: Vesicle fusion or reversible trafficking and de novo conformational coupling? J. Cell Physiol.？2005, 205, 262–269, doi:10.1002/jcp.20399. 15880447
[216]
Woodard, G.E.; Salido, G.M.; Rosado, J.A. Enhanced exocytotic-like insertion of Orai1 into the plasma membrane upon intracellular Ca2+ store depletion. Am. J. Physiol. Cell Physiol.？2008, 294, C1323–C1331.
[217]
Fili, O.; Michaelevski, I.; Bledi, Y.; Chikvashvili, D.; Singer-Lahat, D.; Boshwitz, H.; Linial, M.; Lotan, I. Direct interaction of a brain voltage-gated K+ channel with syntaxin 1A: Functional impact on channel gating. J. Neurosci.？2001, 21, 1964–1974.
[218]
Michaelevski, I.; Chikvashvili, D.; Tsuk, S.; Singer-Lahat, D.; Kang, Y.; Linial, M.; Gaisano, H.Y.; Fili, O.; Lotan, I. Direct interaction of target SNAREs with the Kv2.1 channel. Modal regulation of channel activation and inactivation gating. J. Biol. Chem.？2003, 278, 34320–34330. 12807875
[219]
Tsuk, S.; Michaelevski, I.; Bentley, G.N.; Joho, R.H.; Chikvashvili, D.; Lotan, I. Kv2.1 channel activation and inactivation is influenced by physical interactions of both syntaxin 1A and the syntaxin 1A/soluble N-ethylmaleimide-sensitive factor-25 (t-SNARE) complex with the C terminus of the channel. Mol. Pharmacol.？2005, 67, 480–488. 15525758
[220]
Rossetto, O.; Morbiato, L.; Caccin, P.; Rigoni, M.; Montecucco, C. Presynaptic enzymatic neurotoxins. J. Neurochem.？2006, 97, 1534–1545.
[221]
Li, Y.; Foran, P.; Fairweather, N.F.; de Paiva, A.; Weller, U.; Dougan, G.; Dolly, J.O. A single mutation in the recombinant light chain of tetanus toxin abolishes its proteolytic activity and removes the toxicity seen after reconstitution with native heavy chain. Biochemistry？1994, 33, 7014–7020.
[222]
Yamasaki, S.; Baumeister, A.; Binz, T.; Blasi, J.; Link, E.; Cornille, F.; Roques, B.; Fykse, E.M.; Südhof, T.C.; Jahn, R.; Niemann, H. Cleavage of members of the synaptobrevin/VAMP family by types D and F botulinal neurotoxins and tetanus toxin. J. Biol. Chem.？1994, 269, 12764–12772.
[223]
Ashton, A.C.; Li, Y.; Doussau, F.; Weller, U.; Dougan, G.; Poulain, B.; Dolly, O. Tetanus toxin inhibits neuroexocytosis even when its Zn2+-dependent proteasea ctivity is removed. J. Biol. Chem.？1995, 270, 31386–31390.
[224]
Niemann, H.; Blasi, J.; Jahn, R. Clostridial neurotoxins: New tools for dissecting exocytosis. Trends Cell Biol.？1994, 4, 179–185.
[225]
De Paiva, A.; Ashton, A.C.; Foran, P.; Schiavo, G.; Montecucco, C.; Dolly, J.O. Botulinum A like type B and tetanus toxins fulfils criteria for being a zinc-dependent protease. J. Neurochem.？1993, 61, 2338–2341.
[226]
Cenci Di Bello, I.; Poulain, B.; Shone, C.C.; Tauc, L.; Dolly, J.O. Antagonism of the intracellular action of botulinum neurotoxin type A with monoclonal antibodies that map to light-chain epitopes. Eur. J. Biochem.？1994, 219, 161–169.
[227]
Facchiano, F.; Benfenati, F.; Valtorta, F.; Luini, A. Covalent modification of synapsin I by a tetanus toxin-activated transglutaminase. J. Biol. Chem.？1993, 268, 4588–4591.
[228]
Facchiano, F.; Luini, A. Tetanus toxin potently stimulates tissue transglutaminase. A possible mechanism of neurotoxicity. J. Biol. Chem.？1992, 267, 13267–13271. 1352294
[229]
Coffield, J.A.; Considine, R.V.; Jeyapaul, J.; Maksymowych, A.B.; Zhang, R.D.; Simpson, L.L. The role of transglutaminase in the mechanism of action of tetanus toxin. J. Biol. Chem.？1994, 269, 24454–24458.
[230]
Gobbi, M.; Frittoli, E.; Mennini, T. Role of transglutaminase in [3H]5-HT release from synaptosomes and in the inhibitory effect of tetanus toxin. Neurochem. Int.？1996, 29, 129–134.
[231]
Fesus, L.; Piacentini, M. Transglutaminase 2: An enigmatic enzyme with diverse functions. Trends Biochem. Sci.？2002, 27, 534–539.
Maggio, N.; Sellitti, S.; Capano, C.P.; Papa, M. Tissue-transglutaminase in rat and human brain: light and electron immunocytochemical analysis and in situ hybridization study. Brain Res. Bull.？2001, 56, 173–182.
[234]
Walther, D.J.; Peter, J.U.; Winter, S.; Holtje, M.; Paulmann, N.; Grohmann, M.; Vowinckel, J.; Alamo-Bethencourt, V.; Wilhelm, C.S.; Ahnert-Hilger, G.; Bader, M. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell？2003, 115, 851–862.
[235]
Driscoll, H.K.; Adkins, C.D.; Chertow, T.E.; Cordle, M.B.; Matthews, K.A.; Chertow, B.S. Vitamin A stimulation of insulin secretion: effects on transglutaminase mRNA and activity using rat islets and insulin-secreting cells. Pancreas？1997, 15, 69–77.
[236]
Pastuszko, A.; Wilson, D.F.; Erecinska, M. A role for transglutaminase in neurotransmitter release by rat brain synaptosomes. J. Neurochem.？1986, 46, 499–508.
[237]
Humeau, Y.; Doussau, F.; Vittello, F.; Greengard, P.; Benfenati, F.; Poulain, B. Synapsin controls both reserve and releasable synaptic vesicle pools during neuronal activity and short-term plasticity in Aplysia. J. Neurosci.？2001, 21, 4195–4206.
[238]
Baldelli, P.; Fassio, A.; Valtorta, F.; Benfenati, F. Lack of synapsin I reduces the readily releasable pool of synaptic vesicles at central inhibitory synapses. J. Neurosci.？2007, 27, 13520–13531.
[239]
Presek, P.; Jessen, S.; Dreyer, F.; Jarvie, P.E.; Findik, D.; Dunkley, P.R. Tetanus toxin inhibits depolarization-stimulated protein phosphorylation in rat cortical synaptosomes: Effect on synapsin I phosphorylation and translocation. J. Neurochem.？1992, 59, 1336–1343.
[240]
Dayanithi, G.; Stecher, B.; H？hne-Zell, B.; Yamasaki, S.; Binz, T.; Weller, U.; Niemann, H.; Gratzl, M. Exploring the functional domain and the target of the tetanus toxin light chain in neurophysial terminals. Neuroscience？1994, 58, 423–431.
[241]
DasGupta, B.R.; Tepp, W. Protease activity of botulinum neurotoxin type E and its light chain: Cleavage of actin. Biochem. Biophys. Res. Commun.？1993, 190, 470–474.
[242]
Marxen, P.; Bigalke, H. Tetanus and botulinum A toxins inhibit stimulated F-actin rearrangement in chromaffin cells. Neuroreport？1991, 2, 33–36.
[243]
Eisel, U.; Reynolds, K.; Riddick, M.; Zimmer, A.; Niemann, H.; Zimmer, A. Tetanus toxin light chain expression in Sertoli cells of transgenic mice causes alterations of the actin cytoskeleton and disrupts spermatogenesis. EMBO J.？1993, 12, 3365–3372.
[244]
Ishida, H.; Zhang, X.; Erickson, K.; Ray, P. Botulinum toxin type A targets RhoB to inhibit lysophosphatidic acid-stimulated actin reorganization and acetylcholine release in nerve growth factor-treated PC12 cells. J. Pharmacol. Exp. Ther.？2004, 310, 881–889.
[245]
Nevins, A.K.; Thurmond, D.C. A Direct interaction between Cdc42 and vesicle-associated membrane protein 2 Regulates SNARE-dependent insulin exocytosis. J. Biol. Chem.？2005, 280, 1944–1952.
[246]
Aguilera, J.; Yavin, E. In vivo translocation and down-regulation of protein kinase C following intraventricular administration of tetanus toxin. J. Neurochem.？1990, 54, 339–342.
[247]
Gil, C.; Ruiz-Meana, M.; Alava, M.; Yavin, E.; Aguilera, J. Tetanus toxin enhances protein kinase C activity translocation and increases polyphosphoinositide hydrolysis in rat cerebral cortex preparations. J. Neurochem.？1998, 70, 1636–1643.
[248]
Gil, C.; Chaib-Oukadour, I.; Pelliccioni, P.; Aguilera, J. Activation of signal transduction pathways involving trkA, PLCgamma-1, PKC isoforms and ERK-1/2 by tetanus toxin. FEBS Lett.？2000, 481, 177–182.
[249]
Gil, C.; Chaib-Oukadour, I.; Aguilera, J. C-terminal fragment of tetanus toxin heavy chain activates Akt and MEK/ERK signalling pathways in a Trk receptor-dependent manner in cultured cortical neurons. Biochem. J.？2003, 15, 613–620.
[250]
Chaib-Oukadour, I.; Gil, C.; Aguilera, J. The C-terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death: Involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. J. Neurochem.？2004, 90, 1227–1236.
Mendieta, L.; Venegas, B.; Moreno, N.; Patricio, A.; Martinez, I.; Aguilera, J.; Limon, I.D. The carboxyl-terminal domain of the heavy chain of tetanus toxin prevents dopaminergic degeneration and improves motor behavior in rats with striatal MPP(+)-lesions. Neurosci. Res.？2009, 65, 98–106.
[253]
Chaib-Oukadour, I.; Gil, C.; Aguilera, J. The C-terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death: Involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. J. Neurochem.？2004, 90, 1227–1236.
[254]
Jank, T.; Aktories, K. Structure and mode of action of clostridial glucosylating toxins: The ABCD model. Trends Microbiol.？2008, 16, 222–229.
[255]
Just, I.; Selzer, J.; Wilm, M.; von Eichel-Streiber, C.; Mann, M.; Aktories, K. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature (London)？1995, 375, 500–503.
[256]
Just, I.; Wilm, M.; Selzer, J.; Rex, G.; von Eichel-Streiber, C.; Mann, M.; Aktories, K. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem.？1995, 270, 13932–13936.
[257]
Popoff, M.R.; Chaves-Olarte, E.; Lemichez, E.; Von Eichel-Streiber, C.; Thelestam, M.; Chardin, P.; Cussac, D.; Antonny, B.; Chavrier, P.; Flatau, G.; Giry, M.; de Gunzburg, J.; Boquet, P. Ras, Rap, and rac small GTP-binding proteins are targets for Clostridium sordellii lethal toxin glucosylation. J. Biol. Chem.？1996, 271, 10217–10224.
[258]
Hermann, C.; Ahmadian, M.R.; Hofmann, F.; Just, I. Functional consequences of monoglucosylation of Ha-Ras at effector domain amino acid threonine 35. J. Biol. Chem.？1998, 273, 16134–16139.
[259]
Vetter, I.R.; Hofmann, F.; Wohlgemuth, S.; Hermann, C.; Just, I. Structural consequences of monoglucosylation of Ha-Ras by Clostridium sordellii lethal toxin. J. Mol. Biol.？2000, 301, 1091–1095.
[260]
Popoff, M.R.; Bouvet, P. Clostridial toxins. Future Microbiol.？2009, 4, 1021–1064.
[261]
Aktories, K.; Just, I. Clostridial Rho-inhibiting protein toxins. Curr. Top Microbiol. Immunol.？2005, 291, 113–145.
[262]
Vogelsgesang, M.; Pautsch, A.; Aktories, K. C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins. Naunyn Schmiedebergs Arch. Pharmacol.？2007, 374, 347–360.
[263]
Djouder, N.; Aneiros, E.; Cavalie, A.; Aktories, K. Effects of large clostridial cytotoxins on activation of RBL 2H3-hm1 mast cells indicate common and different roles of Rac in FcepsilonRI and M1-receptor signaling. J. Pharmacol. Exp. Ther.？2003, 304, 1243–1250.
[264]
Gasman, S.; Chasserot-Golaz, S.; Popoff, M.R.; Aunis, D.; Bader, M.F. Involvement of Rho GTPases in calcium-regulated exocytosis from adrenal chromaffin cells. J. Cell Sci.？1999, 112, 4763–4771.
[265]
Kowluru, A.; Li, G.; Rabaglia, M.E.; Segu, V.B.; Hofmann, F.; Aktories, K.; Metz, S.A. Evidence for differential roles of the Rho subfamily of GTP-binding proteins in glucose- and calcium-induced insulin secretion from pancreatic beta cells. Biochem. Pharmacol.？1997, 54, 1097–1108.
[266]
Prepens, U.; Just, I.; von Eichel-Streiber, C.; Aktories, K. Inhibition of Fc epsilon-RI-mediated activation of rat basophilic leukemia cells by Clostridium difficile toxin B (monoglucosyltransferase). J. Biol. Chem.？1996, 271, 7324–7329.
[267]
Barbier, J.; Popoff, M.R.; Molgo, J. Degeneration and regeneration of murine skeletal neuromuscular junctions after intramuscular injection with a sublethal dose of Clostridium sordellii lethal toxin. Infect. Immun.？2004, 72, 3120–3128.
[268]
Geny, B.; Khum, H.; Fitting, C.; Zarantonelli, L.; Mazuet, C.; Cayet, N.; Szatanik, M.; Prevost, M.C.; Cavaillon, J.M.; Huerre, M.; Popoff, M.R. Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability. Am. J. Pathol.？2007, 170, 1003–1017.
[269]
Pothoulakis, C.; Castagliuolo, I.; LaMont, J.T. Nerves and intestinal mast cells modulate responses to enterotoxins. News Physiol. Sci.？1998, 13, 58–63.
[270]
Djouder, N.; Prepens, U.; Aktories, K.; Cavalie, A. Inhibition of calcium release-activated calcium current by Rac/Cdc42-inactivating clostridial cytotoxins in RBL cells. J. Biol. Chem.？2000, 275, 18732–18738.
Ben El Hadj, N.; Popoff, M.R.; Marvaud, J.C.; Payrastre, B.; Boquet, P.; Geny, B. G-protein-stimulated phospholipase D activity is inhibited by lethal toxin from Clostridium sordellii in HL-60 cells. J. Biol. Chem.？1999, 274, 14021–14031.
[273]
Hammond, K.; Caputo, G.A.; London, E. Interaction of the membrane-inserted diphtheria toxin T domain with peptides and its possible implications for chaperone-like T domain behavior. Biochemistry？2002, 41, 3243–3253.
[274]
Meyer, D.K.; Olenik, C.; Hofmann, F.; Barth, H.; Leemhuis, J.; Brunig, I.; Aktories, K.; Norenberg, W. Regulation of somatodendritic GABAA receptor channels in rat hippocampal neurons: Evidence for a role of the small GTPase Rac1. J. Neurosci.？2000, 20, 6743–6751.
[275]
Murray, H.J.; O'Connor, J.J. A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in votro. Brain Res.？2004, 1000, 85–91.
[276]
Triller, A.; Choquet, D. Synaptic structure and diffusion dynamics of synaptic receptors. Biol. Cell？2003, 95, 465–476.
[277]
Linseman, D.A.; Laessig, T.; Meintzer, M.K.; McClure, M.; Barth, H.; Aktories, K.; Heidenreich, K.A. An essential role for Rac/Cdc42 GTPases in cerebellar granule neuron survival. J. Biol. Chem.？2001, 276, 39123–39131.
[278]
Marriott, H.M.; Mitchell, T.J.; Dockrell, D.H. Pneumolysin: A double-edged sword during the host-pathogen interaction. Curr. Mol. Med.？2008, 8, 497–509.
[279]
Rossjohn, J.; Gilbert, R.J.; Crane, D.; Morgan, P.J.; Mitchell, T.J.; Rowe, A.J.; Andrew, P.W.; Paton, J.C.; Tweten, R.K.; Parker, M.W. The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae. J. Mol. Biol.？1998, 284, 449–461.
[280]
Soltani, C.E.; Hotze, E.M.; Johnson, A.E.; Tweten, R.K. Structural elements of the cholesterol-dependent cytolysins that are responsible for their cholesterol-sensitive membrane interactions. Proc. Natl. Acad. Sci. USA？2007, 104, 20226–20231.
[281]
Mitchell, T.J. Pneumolysin: Structure, function, and role in disease. In The Sourcebook of Bacterial Protein Toxins, 3rd; Alouf, J.E., Popoff, M.R., Eds.; Elsevier Academic Press: Amsterdam, The Netherland, 2006; pp. 680–699.
[282]
Soltani, C.E.; Hotze, E.M.; Johnson, A.E.; Tweten, R.K. Specific protein-membrane contacts are required for prepore and pore assembly by a cholesterol-dependent cytolysin. J. Biol. Chem.？2007, 282, 15709–15716.
[283]
Shepard, L.; Shatursky, O.; Johnson, A.; Tweten, R. The mechanism of pore assembly for a cholesterol-dependent cytolysin: formation of a large prepore complex precedes the insertion of hte transmembrane b-hairpins. Biochemistry？2000, 39, 10284–10293.
[284]
Dang, T.X.; Hotze, E.M.; Rouiller, I.; Tweten, R.K.; Wilson-Kubalek, E.M. Prepore to pore transition of a cholesterol-dependent cytolysin visualized by electron microscopy. J. Struct. Biol.？2005, 150, 100–108.
Heuck, A.P.; Savva, C.G.; Holzenburg, A.; Johnson, A.E. Conformational changes that effect oligomerization and initiate pore formation are triggered throughout perfringolysin O upon binding to cholesterol. J. Biol. Chem.？2007, 282, 22629–22637.
[287]
Rossjohn, J.; Polekhina, G.; Feil, S.C.; Morton, C.J.; Tweten, R.K.; Parker, M.W. Structures of perfringolysin O suggest a pathway for activation of cholesterol-dependent cytolysins. J. Mol. Biol.？2007, 367, 1227–1236.
[288]
Ramachandran, R.; Heuck, A.P.; Tweten, R.K.; Johnson, A.E. Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin. Nat. Struct. Biol.？2002, 9, 823–827.
[289]
Heuck, A.P.; Hotze, E.M.; Tweten, R.K.; Johnson, A.E. Mechanism of membrane insertion of a multimeric beta-barrel protein: Perfringolysin O creates a pore using ordered and coupled conformational changes. Mol. Cell.？2000, 6, 1233–1242.
Shatursky, O.; Heuck, A.; Shepard, L.; Rossjhon, J.; Parker, M.; Johnson, A.; Tweten, R. The mechanism of membrane insertion of a cholesterol-dependent cytolysin: A novel paradigm for pore-forming toxins. Cell？1999, 99, 293–299.
[292]
Hotze, E.M.; Heuck, A.P.; Czajkowsky, D.M.; Shao, Z.; Johnson, A.E.; Tweten, R.K. Monomer-monomer interactions drive the prepore to pore conversion of a β-barrel-forming cholesterol-dependent cytolysin. J. Biol. Chem.？2002, 277, 11597–11605.
[293]
Rossjohn, J.; Feil, S.C.; McKinstry, W.J.; Tweten, R.K.; Parker, M.W. Structure of a cholesterol-binding thiol-activated cytolysin and a model of its membrane form. Cell？1997, 89, 685–692.
[294]
Czajkowsky, D.M.; Hotze, E.M.; Shao, Z.; Tweten, R.K. Vertical collapse of a cytolysin prepore moves its transmembrane beta-hairpins to the membrane. Embo J.？2004, 23, 3206–3215.
[295]
Hirst, R.A.; Kadioglu, A.; O'Callaghan, C.; Andrew, P.W. The role of pneumolysin in pneumococcal pneumonia and meningitis. Clin. Exp. Immunol.？2004, 138, 195–201.
[296]
Braun, J.S.; Sublett, J.E.; Freyer, D.; Mitchell, T.J.; Cleveland, J.L.; Tuomanen, E.I.; Weber, J.R. Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis. J. Clin. Invest.？2002, 109, 19–27.
[297]
Braun, J.S.; Hoffmann, O.; Schickhaus, M.; Freyer, D.; Dagand, E.; Bermpohl, D.; Mitchell, T.J.; Bechmann, I.; Weber, J.R. Pneumolysin causes neuronal cell death through mitochondrial damage. Infect. Immun.？2007, 75, 4245–4254.
[298]
Stringaris, A.K.; Geisenhainer, J.; Bergmann, F.; Balshusemann, C.; Lee, U.; Zysk, G.; Mitchell, T.J.; Keller, B.U.; Kuhnt, U.; Gerber, J.; Spreer, A.; Bahr, M.; Michel, U.; Nau, R. Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase. Neurobiol. Dis.？2002, 11, 355–368.
[299]
Goldstein, J.; Morris, W.E.; Loidl, C.F.; Tironi-Farinatti, C.; McClane, B.A.; Uzal, F.A.; Fernandez Miyakawa, M.E. Clostridium perfringens epsilon toxin increases the small intestinal permeability in mice and rats. PLoS One？2009, 4, e7065.
[300]
Losada-Eaton, D.M.; Uzal, F.A.; Fernandez Miyakawa, M.E. Clostridium perfringens epsilon toxin is absorbed from different intestinal segments of mice. Toxicon？2008, 51, 1207–1213.
[301]
Finnie, J.W. Pathogenesis of brain damage produced in sheep by Clostridium perfringens type D epsilon toxin: A review. Aust. Vet J.？2003, 81, 219–221.
Buxton, D. The use of an imunoperoxidase technique to investigate by light and electron microscopy the sites of binding of Clostridium welchii type D e-toxin in mice. J. Med. Microbiol.？1978, 11, 289–292.
[307]
Finnie, J.W.; Blumbergs, P.C.; Manavis, J. Neuronal damage produced in rat brains by Clostridium perfringens type D epsilon-toxin. J. Comp. Path.？1999, 120, 415–420.
[308]
Miyamoto, O.; Minami, J.; Toyoshima, T.; Nakamura, T.; Masada, T.; Nagao, S.; Negi, T.; Itano, T.; Okabe, A. Neurotoxicity of Clostridium perfringens epsilon-toxin for the rat hipocampus via glutamanergic system. Infect. Immun.？1998, 66, 2501–2508.
[309]
Miyamoto, O.; Sumitami, K.; Nakamura, T.; Yamagani, S.; Miyatal, S.; Itano, T.; Negi, T.; Okabe, A. Clostridium perfringens epsilon toxin causes excessive release of glutamate in the mouse hippocampus. FEMS Microbiol. Lett.？2000, 189, 109–113.
[310]
Cole, A.R.; Gibert, M.; Popoff, M.R.; Moss, D.S.; Titball, R.W.; Basak, A. Clostridium perfringens ε-toxin shows structural similarity to the pore-forming toxin aerolysin. Nat. Struct. Mol. Biol.？2004, 11, 797–798.
[311]
Knapp, O.; Maier, E.; Benz, R.; Geny, B.; Popoff, M.R. Identification of the channel-forming domain of Clostridium perfringens Epsilon-toxin (ETX). Biochim. Biophys. Acta？2009, 1788, 2584–2593.
[312]
Cole, A. Structural studies on epsilon toxin from Clostridium perfringens. In Protein Toxins of the Genus Clostridium and Vaccination; Duchesnes, C., Mainil, J., Popoff, M.R., Titball, R., Eds.; Presses de la Faculté de Médecine Vétérinaire: Liège, Montreal, Canada, 2003; p. 95.
[313]
Miyata, S.; Minami, J.; Tamai, E.; Matsushita, O.; Shimamoto, S.; Okabe, A. Clostridium perfringens ε-toxin forms a heptameric pore within the detergent-insoluble microdomains of Madin-Darby Canine Kidney Cells and rat synaptosomes. J. Biol. Chem.？2002, 277, 39463–39468.
[314]
Petit, L.; Gibert, M.; Gillet, D.; Laurent-Winter, C.; Boquet, P.; Popoff, M.R. Clostridium perfringens epsilon-toxin acts on MDCK cells by forming a large membrane complex. J. Bacteriol.？1997, 179, 6480–6487.
[315]
Petit, L.; Maier, E.; Gibert, M.; Popoff, M.R.; Benz, R. Clostridium perfringens epsilon-toxin induces a rapid change in cell membrane permeability to ions and forms channels in artificial lipid bilayers. J. Biol. Chem.？2001, 276, 15736–15740.
[316]
Petit, P.; Breard, J.; Montalescol, V.; Ben El Hadj, N.; Levade, T.; Popoff, M.R.; Geny, B. Lethal toxin from Clostridium sordellii induces apoptotic cell death by disruption of mitochondrial homeostasis in HL-60 cells. Cell. Miccrobiol.？2003, 5, 761–771.
[317]
Miyata, S.; Matsushita, O.; Minami, J.; Katayama, S.; Shimamoto, S.; Okabe, A. Cleavage of C-terminal peptide is essential for heptamerization of Clostridium perfringens ε-toxin in the synaptosomal membrane. J. Biol. Chem.？2001, 276, 13778–13783.
[318]
Petit, L.; Gibert, M.; Gourch, A.; Bens, M.; Vandewalle, A.; Popoff, M.R. Clostridium perfringens Epsilon Toxin rapidly decreases membrane barrier permeability of polarized MDCK Cells. Cell. Microbiol.？2003, 5, 155–164.
[319]
Chassin, C.; Bens, M.; de Barry, J.; Courjaret, R.; Bossu, J.L.; Cluzeaud, F.; Ben Mkaddem, S.; Gibert, M.; Poulain, B.; Popoff, M.R.; Vandewalle, A. Pore-forming epsilon toxin causes membrane permeabilization and rapid ATP depletion-mediated cell death in renal collecting duct cells. Am. J. Physiol. Renal. Physiol.？2007, 293, F927–F937.
[320]
Farthing, M.J. Enterotoxins and the enteric nervous system--a fatal attraction. Int. J. Med. Microbiol.？2000, 290, 491–496.
Hirst, T.R.; D'Souza, J.M. Vibrio cholerae and Escherichia coli thermolabile enterotoxin. In The Sourcebook of Bacterial Protein Toxins, 3rd; Alouf, J.E., Popoff, M.R., Eds.; Elmsevier Academic Press: Amsterdam, The Netherland, 2006; pp. 270–290.
[323]
Holmes, R.K.; Jobling, M.G.; Conell, T.D. Cholera toxin and related enterotoxins of Gram-negative bacteria. In Bacterial Toxins and Virulence Factors in Disease; Moss, J., Iglewski, B., Vaughan, M., Tu, A.T., Eds.; Marcel Dekker: New York, NY, USA, 1995; pp. 225–255.
[324]
de Haan, L.; Hirst, T.R. Cholera toxin: A paradigm for multi-functional engagement of cellular mechanisms. Mol. Membr. Biol.？2004, 21, 77–92.
[325]
Nichols, B.J. A distinct class of endosome mediates clathrin-independent endocytosis to the Golgi complex. Nat. Cell Biol.？2002, 4, 374–378.
[326]
Fujinaga, Y.; Wolf, A.A.; Rodighiero, C.; Wheeler, H.E.; Tsai, B.; Allen, L.; Jobling, M.G.; Rapoport, T.; Holmes, R.K.; Lencer, W.I. Gangliosides that associate with lipid rafts mediate transport of cholera and related toxins from the plasma membrane to endoplasmic reticulum. Mol. Biol. Cell？2003, 14, 4783–4793.
[327]
Johannes, L.; Tenza, D.; Antony, C.; Goud, B. Retrograde transport of KDEL-bearing B-fragment of Shiga toxin. J. Biol. Chem.？1997, 272, 19554–19561.
[328]
Lundgren, O. 5-Hydroxytryptamine, enterotoxins, and intestinal fluid secretion. Gastroenterology？1998, 115, 1009–1012.
[329]
Turvill, J.L.; Mourad, F.H.; Farthing, M.J. Crucial role for 5-HT in cholera toxin but not Escherichia coli heat-labile enterotoxin-intestinal secretion in rats. Gastroenterology？1998, 115, 883–890.
[330]
Mourad, F.H.; O'Donnell, L.J.; Dias, J.A.; Ogutu, E.; Andre, E.A.; Turvill, J.L.; Farthing, M.J. Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins. Gut？1995, 37, 340–345.
[331]
Bearcroft, C.P.; Perrett, D.; Farthing, M.J. 5-hydroxytryptamine release into human jejunum by cholera toxin. Gut？1996, 39, 528–531.
[332]
Nilsson, O.; Cassuto, J.; Larsson, P.A.; Jodal, M.; Lidberg, P.; Ahlman, H.; Dahlstrom, A.; Lundgren, O. 5-Hydroxytryptamine and cholera secretion: A histochemical and physiological study in cats. Gut？1983, 24, 542–548.
[333]
Beubler, E.; Horina, G. 5-HT2 and 5-HT3 receptor subtypes mediate cholera toxin-induced intestinal fluid secretion in the rat. Gastroenterology？1990, 99, 83–89.
[334]
Buchheit, K.H. Inhibition of cholera toxin-induced intestinal secretion by the 5-HT3 receptor antagonist ICS 205–930. Naunyn Schmiedebergs Arch. Pharmacol.？1989, 339, 704–705.
[335]
Beattie, D.T.; Smith, J.A. Serotonin pharmacology in the gastrointestinal tract: A review. Naunyn Schmiedebergs Arch. Pharmacol.？2008, 377, 181–203.
[336]
Cooke, H.J. Neurotransmitters in neuronal reflexes regulating intestinal secretion. Ann. NY Acad. Sci.？2000, 915, 77–80.
[337]
Lundgren, O. Enteric nerves and diarrhoea. Pharmacol. Toxicol.？2002, 90, 109–120.
[338]
Turvill, J.L.; Connor, P.; Farthing, M.J. Neurokinin 1 and 2 receptors mediate cholera toxin secretion in rat jejunum. Gastroenterology？2000, 119, 1037–1044.
[339]
Castagliuolo, I.; Lamont, J.T.; Letourneau, R.; Kelly, C.; O'Keane, J.C.; Jaffer, A.; Theoharides, T.C.; Pothoulakis, C. Neuronal involvement in the intestinal effects of Clostridium difficile Toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology？1994, 107, 657–665.
[340]
Pothoulakis, C.; Lamont, J.T. Microbes and microbial toxins: paradigms for microbial-mucosa interactions II. The integrated response of the intestine to Clostridium difficile toxins. Am. J. Physiol. Gastrointest. Liver Physiol.？2001, 280, G178–G183. 11208538
[341]
Castagliuolo, I.; Riegler, M.; Pasha, A.; Nikulasson, S.; Lu, B.; Gerard, C.; Gerard, N.P.; Pothoulakis, C. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis. J. Clin. Invest.？1998, 101, 1547–1550.
[342]
Castagliuolo, I.; Wang, C.C.; Valenick, L.; Pasha, A.; Nikulasson, S.; Carraway, R.E.; Pothoulakis, C. Neurotensin is a proinflammatory peptide in colonic inflammation. J. Clin. Invest.？1999, 103, 843–849.
[343]
Xia, Y.; Hu, H.Z.; Liu, S.; Pothoulakis, C.; Wood, J.D. Clostridium difficile toxin A excites enteric neurones and suppresses sympathetic neurotransmision in the guinea pig. Gut？2000, 46, 481–486.
[344]
McClane, B.A. Clostridium perfringens enterotoxin. In The Cmprehensive Sourcebook of Bacterial Protein Toxins, 3rd; Alouf, J.E., Popoff, M.R., Eds.; Elsevier Academic Press: Amsterdam, The Netherland, 2006; pp. 763–778.
[345]
Senda, T.; Sugimoto, N.; Horiguchi, Y.; Matsuda, M. The enterotoxin of Clostridium perfringens type A binds to the presynaptic nerve endings in neuromuscular junctions of mouse phrenic nerve-diaphragm. Toxicon？1995, 33, 499–506.
[346]
Rolfe, V.E.; Levin, R.J. Vagotomy inhibits the jejunal fluid secretion activated by luminal ileal Escherichia coli STa in the rat in vivo. Gut？1999, 44, 615–619.
[347]
Mourad, F.H.; Nassar, C.F. Effect of vasoactive intestinal polypeptide (VIP) antagonism on rat jejunal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins. Gut？2000, 47, 382–386.
[348]
Rolfe, V.; Levin, R.J. Enterotoxin Escherichia coli STa activates a nitric oxide-dependent myenteric plexus secretory reflex in the rat ileum. J. Physiol.？1994, 475, 531–537.
[349]
Eklund, S.; Jodal, M.; Lundgren, O. The enteric nervous system participates in the secretory response to the heat stable enterotoxins of Escherichia coli in rats and cats. Neuroscience？1985, 14, 673–681.
[350]
Stenfors Arnesen, L.P.; Fagerlund, A.; Granum, P.E. From soil to gut: Bacillus cereus and its food poisoning toxins. FEMS Microbiol. Rev.？2008, 32, 579–606.
[351]
Toh, M.; Moffitt, M.C.; Henrichsen, L.; Raftery, M.; Barrow, K.; Cox, J.M.; Marquis, C.P.; Neilan, B.A. Cereulide, the emetic toxin of Bacillus cereus, is putatively a product of nonribosomal peptide synthesis. J. Appl. Microbiol.？2004, 97, 992–1000.
[352]
Agata, N.; Ohta, M.; Mori, M.; Isobe, M. A novel dodecadepsipeptide, cereulide, is an emetic toxin of Bacillus cereus. FEMS Microbiol. Lett.？1995, 129, 17–20.
[353]
Horwood, P.F.; Burgess, G.W.; Oakey, H.J. Evidence for non-ribosomal peptide synthetase production of cereulide (the emetic toxin) in Bacillus cereus. FEMS Microbiol. Lett.？2004, 236, 319–324.
[354]
Agata, N.; Ohta, M.; Mori, M. Production of an emetic toxin, cereulide, is associated with a specific class of Bacillus cereus. Curr. Microbiol.？1996, 33, 67–69.
[355]
Shinagawa, K.; Konuma, H.; Sekita, H.; Sugii, S. Emesis of rhesus monkeys induced by intragastric administration with the HEp-2 vacuolation factor (cereulide) produced by Bacillus cereus. FEMS Microbiol. Lett.？1995, 130, 87–90.
[356]
Agata, N.; Mori, M.; Ohta, M.; Suwan, S.; Ohtani, I.; Isobe, M. A novel dodecadepsipeptide, cereulide, isolated from Bacillus cereus causes vacuole formation in HEp-2 cells. FEMS Microbiol. Lett.？1994, 121, 31–34.
[357]
Yokoyama, K.; Ito, M.; Agata, N.; Isobe, M.; Shibayama, K.; Horii, T.; Ohta, M. Pathological effect of synthetic cereulide, an emetic toxin of Bacillus cereus, is reversible in mice. FEMS Immunol. Med. Microbiol.？1999, 24, 115–120.
[358]
Virtanen, S.M.; Roivainen, M.; Andersson, M.A.; Ylipaasto, P.; Hoornstra, D.; Mikkola, R.; Salkinoja-Salonen, M.S. In vitro toxicity of cereulide on porcine pancreatic Langerhans islets. Toxicon？2008, 51, 1029–1037.
[359]
Andersson, M.A.; Hakulinen, P.; Honkalampi-Hamalainen, U.; Hoornstra, D.; Lhuguenot, J.C.; Maki-Paakkanen, J.; Savolainen, M.; Severin, I.; Stammati, A.L.; Turco, L.; Weber, A.; von Wright, A.; Zucco, F.; Salkinoja-Salonen, M. Toxicological profile of cereulide, the Bacillus cereus emetic toxin, in functional assays with human, animal and bacterial cells. Toxicon？2007, 49, 351–367, doi:10.1016/j.toxicon.2006.10.006. 17156808
[360]
Mikkola, R.; Saris, N.E.; Grigoriev, P.A.; Andersson, M.A.; Salkinoja-Salonen, M.S. Ionophoretic properties and mitochondrial effects of cereulide: the emetic toxin of B. cereus. Eur. J. Biochem.？1999, 263, 112–117.
[361]
Teplova, V.V.; Mikkola, R.; Tonshin, A.A.; Saris, N.E.; Salkinoja-Salonen, M.S. The higher toxicity of cereulide relative to valinomycin is due to its higher affinity for potassium at physiological plasma concentration. Toxicol. Appl. Pharmacol.？2006, 210, 39–46.
[362]
Saris, N.E.; Andersson, M.A.; Mikkola, R.; Andersson, L.C.; Teplova, V.V.; Grigoriev, P.A.; Salkinoja-Salonen, M.S. Microbial toxin's effect on mitochondrial survival by increasing K+ uptake. Toxicol. Ind. Health.？2009, 25, 441–446.
[363]
Krakauer, T.; Stiles, B.G. Staphylococcal enterotoxins, toxic-shock syndrome toxin-1, and streptococcal pyrogenic exotoxins: Some basic biology of bacterial superantigens. Rec. Res. Dev. Infect. Immun.？2003, 1, 21–27.
[364]
Jett, M.; Brinkley, W.; Neill, R.; Gemski, P.; Hunt, R. Staphylococcus aureus enterotoxin B challenge of monkeys: Correlation of plasma levels of arachidonic acid cascade products with occurrence of illness. Infect. Immun.？1990, 58, 3494–3499.
[365]
Alber, G.; Scheuber, P.H.; Reck, B.; Sailer-Kramer, B.; Hartmann, A.; Hammer, D.K. Role of substance P in immediate-type skin reactions induced by staphylococcal enterotoxin B in unsensitized monkeys. J. Allergy Clin. Immunol.？1989, 84, 880–885.
[366]
Tiegs, G.; Bang, R.; Neuhuber, W.L. Requirement of peptidergic sensory innervation for disease activity in murine models of immune hepatitis and protection by beta-adrenergic stimulation. J. Neuroimmunol.？1999, 96, 131–143.
[367]
Wang, X.; Wang, B.R.; Zhang, X.J.; Duan, X.L.; Guo, X.; Ju, G. Fos expression in the rat brain after intraperitoneal injection of Staphylococcus enterotoxin B and the effect of vagotomy. Neurochem. Res.？2004, 29, 1667–1674.
[368]
Hu, D.L.; Zhu, G.; Mori, F.; Omoe, K.; Okada, M.; Wakabayashi, K.; Kaneko, S.; Shinagawa, K.; Nakane, A. Staphylococcal enterotoxin induces emesis through increasing serotonin release in intestine and it is downregulated by cannabinoid receptor 1. Cell Microbiol.？2007, 9, 2267–2277.
