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Chapter 3: Molecular basis for the therapeutic effectiveness of botulinum neurotoxin type A
Author(s) -
Dolly J. Oliver,
Lawrence Gary W.
Publication year - 2014
Publication title -
neurourology and urodynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 90
eISSN - 1520-6777
pISSN - 0733-2467
DOI - 10.1002/nau.22634
Subject(s) - exocytosis , synaptic vesicle , neurotransmission , microbiology and biotechnology , neurotoxin , acetylcholine , neuroscience , chemistry , medicine , pharmacology , vesicle , biology , biochemistry , secretion , receptor , membrane
The utility of botulinum neurotoxin type A (BoNT/A) for treating overactive muscles and endocrine glands is attributable to a unique conflation of properties honed to exploit and inactivate synaptic transmission. Specific, high‐affinity coincident binding to gangliosides plus an intraluminal loop of synaptic vesicle protein 2 (SV2) by the heavy chain (HC) of BoNT/A confers selectivity for presynaptic nerve terminals and subsequent uptake by endocytosis. Upon vesicle acidification, the HC forms a channel for transmembrane transfer of the light chain to the cytosol, as observed by single channel recordings. The light chain is a Zn 2+ ‐dependent endoprotease that cleaves and inactivates SNAP‐25, thereby blocking exocytotic release of transmitters, a discovery that revealed the pivotal role of the latter in synaptic vesicle fusion. A di‐leucine motif in BoNT/A light chain stabilizes this protease, contributing to its longevity inside nerves. The ubiquity of SV2 and SNAP‐25 has prompted re‐evaluation of the nerve types susceptible to BoNT/A. In urology, there is emerging evidence that BoNT/A blocks neuropeptide release from afferent nerves, exocytosis of acetylcholine and purines from efferent nerves, and possibly ATP release from the urothelium. Suppression by BoNT/A of the surface expression of nociceptor channels on bladder afferents might also contribute to its improvement of urological sensory symptoms. Neurourol. Urodynam. 33:S14–S20, 2014 . © 2014 Wiley Periodicals, Inc.