Mechanism of Botulinum Toxin a Neurotoxicity: Channel Formation and ProteinPhosphorylation

摘要

A unique contribution of this program is the discovery of potentiation ofbotulinum neurotoxin (BoTx) A protease activity by tyrosine phosphorylation. This key finding underscores the requirement to screen for potential blockers using the pharmacologically relevant target, namely tyrosine phosphorylated neurotoxin, presumably the biologically active form within the cells. A most exciting outcome is the ability to design peptides that selectively block neurotransmitter release. The proteolytic products of the BoTx activity have proved to be instrumental in providing clues about the secretory vesicle fusion process. These peptides are suitable mimics of the neurotoxin itself, displaying effective inhibitory activity on transmitter release by inhibiting vesicle docking and thereby disabling the fusion machinery. Peptides designed along these principles may find clinical application as BoTx substitutes in the treatment or management of disorders associated with involuntary muscle spasms. A major finding is the identification of an ion channel-forming motif in BoTxA heavy chain. The ion channel activity of BoTx may be abrogated by identifying effective open channel blockers, lending credence to the concept that open channel blockers may be a single class of drugs effective against all BoTxs isoforms. The potency of such agents may, in principle, be augmented by combining active compounds against both the protease and channel activities of the neurotoxin which are considered necessary for its neurotoxicity.