Video transcript: Botox mechanism of action

botulinum_toxin_moa The presynaptic neuromuscular nerve ending contains vesicles prepared to release the neurotransmitter acetylcholine. Neuronal stimulation initiates a cascade of events that leads to the fusion of the neurotransmitter containing vesicle with the nerve membrane. This process is facilitated by a group of proteins comprising the SNARE complex. The membrane fusion results in the release of acetylcholine into the synaptic cleft by a process of exocytosis.

Acetylcholine diffuses and eventually binds to acetylcholine receptors in the muscle, leading to muscle contraction.

Botox (botulinum toxin type A) consists of a heavy chain of 100 kDa and a light chain of 50 kDa making up the 150 kDa core type A molecule. The toxin is protected by accessory hemaglutinin and non-toxic non- hemaglutinin proteins.

This illustration shows a cross section of the spine, with a motor neuron extending into the muscle and a sensory neuron extending out of the muscle. After injection of Botox it would be expected that most of the neurotoxin would remain in the injection site. The Botox core molecule dissociates from the accessory proteins and targets the nerve endings. The binding domain of the Botox core molecule is the C-terminal portion of the heavy chain.

The Botox core molecule enters the nerve cell by a process of receptor mediated endocytosis. It is the heavy chain that contains the binding domain. The toxin is now contained in a membranous vesicle inside the cell. Soon after, the light chain is released into the cytoplasm of nerve terminal, where it begins to cleave one of the SNARE proteins.

In motor neurons, the light chain of the Botox core molecule blocks the release of acetylcholine by cleaving SNAP-25, which is an essential component of the SNARE complex. When acetylcholine cannot be released, muscle contraction cannot occur. In sensory neurons, the light chain is believed to cleave SNAP-25 by a similar mechanism, thereby blocking the release of neuropeptide neurotransmitters and inhibiting the desensitation of pain nerves.

The toxin does not appear to affect the conduction along the nerve fiber or the synthesis or storage of acetylcholine.

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