Mechanism of Action of Botulinum Toxin

MECHANISM OF ACTION:-

•    A, Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex that allows the membrane of the synaptic vesicle containing acetylcholine to fuse with the neuronal cell membrane.

•    The synaptic fusion complex is a set of SNARE proteins, which include synaptobrevin, SNAP-25, and syntaxin.

•    After membrane fusion, acetylcholine is released into the synaptic cleft and then bound by receptors on the muscle cell.

•    B, Botulinum toxin binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis.

•    The light chain of botulinum toxin cleaves specific sites on the SNARE proteins, preventing complete assembly of the synaptic fusion
    complex and thereby blocking acetylcholine release. Botulinum toxins types B, D, F, and G cleave synaptobrevin; types A, C, and E
     cleave SNAP-25; and type C cleaves syntaxin.

•    Without acetylcholine release, the muscle is unable to contract. SNARE indicates soluble NSF-attachment protein receptor; NSF,
     N-ethylmaleimide-sensitive fusion protein; and SNAP-25, synaptosomal-associated protein of 25 kd.
 
•    Target molecules of botulinum (BoNT) and tetanus (TeNT) toxins inside the axon terminal.

•    The heavy chain of the toxin is particularly important for targeting the toxin to specific types of axon terminals. The toxin must get inside
     the axon terminals in order to cause paralysis. Following the attachment of the toxin heavy chain to proteins on the surface of axon
     terminals, the toxin can be taken into neurons by endocytosis. The light chain is able to leave endocytotic vesicles and reach the
     cytoplasm. The light chain of the toxin has protease activity.

•    The type a toxin proteolytically degrades the SNAP-25 protein, a type of SNARE protein. The SNAP-25 protein is required for the release
     of neurotransmitters from the axon endings.[24] Botulinum toxin specifically cleaves these SNAREs, and so prevents neuro-secretory
     vesicles from docking/fusing with the nerve synapse plasma membrane and releasing their neurotransmitters.

•    Though it affects the nervous system, common nerve agent treatments (namely the injection of atropine and 2-pam-chloride) will increase
       mortality by enhancing botulin toxin's mechanism of toxicity.

•    Attacks involving botulinum toxin are distinguishable from those involving nerve agent in that NBC detection equipment (such as M-8
     paper or the ICAM) will not indicate a "positive" when a sample of the agent is tested. Furthermore, botulism symptoms develop relatively
     slowly, over several days compared to nerve agent effects, which can be instantaneous.