title: Chapter 3: Molecular basis for the therapeutic effectiveness of botulinum neurotoxin type A.
abstract: 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.
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin, Ireland.
authors.forename: J Oliver
authors.initials: JO
authors.lastname: Dolly
authors.forename: Gary W
authors.initials: GW
authors.lastname: Lawrence
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000009:adverse effects / Q000627:therapeutic use*; D004525:Efferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004705:Endocytosis / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D009465:Neuromuscular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D016896:Treatment Outcome; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation*; D001750:Urinary Bladder, Neurogenic / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A
keywords: P2X3; SNAP-25; SV2; TRPV1; cholinergic; exo-/endocytosis; purinergic; transmitters