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Pathways Blockade of Neurotransmitter Relase by Botulinum Toxin
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Description: Description: The neuromuscular junction communicates action potentials from motor neurons across a synapse to skeletal muscle. When an action impulse arrives at the neuromuscular junction, the entry of calcium through voltage-gated calcium channels causes synaptic vesicles to fuse with the presynaptic plasma membrane and release the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine diffuses across the cleft and binds to muscle acetylcholine receptors, causing depolarization and an action potential that travels throughout the length of the muscle cell triggering muscle contraction.

The release of neurotransmitter at the synapse involves the fusion of synaptic vesicles with the neuronal plasma membrane and requires several proteins that act together to form a synaptic fusion complex. These proteins, collectively called SNARE proteins, include SNAP-25, syntaxin, and synaptobrevin. Homologs of these proteins are also involved in membrane fusion in other aspects of vesicle trafficking. Synaptobrevin (also called VAMP2) is localized at the synaptic vesicle membrane, while SNAP-25 and syntaxin are associated with the plasma membrane. Calcium release causes the formation of a complex, bringing the synaptic vesicle in close proximity with the plasma membrane and allowing fusion of the membranes.

Biological toxins often disrupt nervous function, particularly the action of motor neurons. Botulinum toxin, synthesized by the bacteria Clostridium botulinum, is one of the most potent toxins known and acts by blocking neurotransmitter release at the neuromuscular junction. Botulinum toxin is a protein composed of two subunits joined by a disulfide bond, a 100 kD heavy subunit and a 50 kD light subunit that is a protease. There are seven serotypes of botulinum with distinct toxins. Tetanus toxin is similar in structure and in mechanism of action to botulinum toxin. The toxins can be absorbed in the intestine to travel in the blood to its site of action, at the neuromuscular junction. At the synapse botulinum toxin binds to the presynaptic membrane, and large subunit mediates internalization into the neuron through endocytosis. Once inside the neuron, the light chain is translocated across the vesicular membrane to act as a protease on cytoplasmic substrates. The targets of the toxin protease include the components of the synaptic fusion complex. Tetanus toxin and botulinum B, D, F and G toxins degrade synaptobrevin, while botulinum A, C and E toxins cleave SNAP-25. Syntaxin is also targeted by serotype C toxin. Destruction of these proteins by botulinum toxin prevents vesicular fusion in response to action potentials, blocking the release of acetylcholine. This blockade of communication between the nervous system and skeletal muscle can cause paralysis and can lead to death if the paralysis is severe enough to prevent breathing.

In addition to acting as a toxin during botulism infection, botulinum toxin is also now being used as a pharmaceutical. Careful administration of very small doses of toxin can restrict its action locally to reduce overactive muscles, such as those involved in twitching of the eyes. Relaxing the muscles around the eyes can also reduce wrinkles in the eye region, leading to cosmetic use of this potent bacterial toxin. The potency of botulinum toxin has also caused concern that it could be used as a biological weapon, creating interest in the identification of inhibitors of this toxin.
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Description: Description:
references: references: Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton M, Lillibridge S, Osterholm MT, OToole T, Parker G, Perl TM, Russell PK, Swerdlow DL, Tonat K. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001 Feb 28;285(8):1059-70. Review.

Blasi J. et al. (1993) Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365(6442), 160-3

Chen, Y.A., Scales, S.J., Patel, S.M., Doung, Y.C., Scheller, R.H. (1999) SNARE complex formation is triggered by Ca2+ and drives membrane fusion. Cell 97(2), 165-74

Chen, Y.A., Scales, S.J., Scheller, R.H. (2001) Sequential SNARE assembly underlies priming and triggering of exocytosis. Neuron 30(1), 161-70

Loranger SS, Linder ME. SNAP-25 traffics to the plasma membrane by a syntaxin-independent mechanism. J Biol Chem. 2002 Jul 11

OConnor V. et al. (1997) Disruption of syntaxin-mediated protein interactions blocks neurotransmitter secretion. Proc Natl Acad Sci U S A 94(22), 12186-91

Schiavo G. et al. (1992) Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359(6398), 832-5

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