title: Neuro-exocytosis: botulinum toxins as inhibitory probes and versatile therapeutics.
abstract: For the fundamental process of quantal neurotransmitter release, a consensus is being reached on the recycling pathways for transmitter-containing, small synaptic vesicles (SSVs), and major inroads have been made into deciphering the multiple steps of regulated exocytosis. These advances arose from the identification of approximately 80 proteins in SSVs, elucidation of the structures of pertinent macromolecular complexes, utilisation of different serotypes (A-G) of botulinum neurotoxin (BoNT) together with transgenic mice lacking key genes. Hence, converging evidence continues to emerge for the sequential formation of complexes between the three SNAREs (SNAP-25, syntaxin and VAMP) and their regulatory proteins (complexins, Munc18), as well as for the Ca2+ triggering of membrane fusion/exocytosis via its sensor, synaptotagmin. Moreover, molecular data gained on BoNTs have been translated into Clinical Medicine with type A now being applied worldwide for effectively treating >100 human conditions due to overactivity of nerves supplying various muscles or glands. A recent advance is the successful engineering of a chimera from two BoNTs to acquire the capability of re-targeting a more active moiety to sensory neurons, with resultant inhibition of the release of a pain mediator. Encouragingly, this novel recombinant protein blocks the exocytotic response triggered by a stimulant (capsaicin) of nociceptive C fibres that activates their vanilloid receptors, a feat not possible for either parental toxin. Reaching this landmark has generated optimism for designing further variants of such a versatile therapeutic for normalising the hyper-activity of particular cell types, especially those underlying the many cases of chronic pain that do not respond to existing drugs.
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland. oliver.dolly@dcu.ie
authors.forename: J Oliver
authors.initials: JO
authors.lastname: Dolly
authors.forename: Gary W
authors.initials: GW
authors.lastname: Lawrence
authors.forename: Jianghui
authors.initials: J
authors.lastname: Meng
authors.forename: Jiafu
authors.initials: J
authors.lastname: Wang
authors.forename: Saak V
authors.initials: SV
authors.lastname: Ovsepian
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D005089:Exocytosis / Q000187:drug effects*; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D050600:SNARE Proteins / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D050600:SNARE Proteins; D001905:Botulinum Toxins; D002118:Calcium