Preferred Label : Botulin Pathway;
NCIt related terms : Blockade of Neurotransmitter Relase by Botulinum Toxin;
Alternative definition : BIOCARTA: The neuromuscular junction communicates action potentials from motor neurons
across a synapse to skeletal muscle. When an action impulse arrives at the neuromuscular
junction, the entry of calcium through voltage-gated calcium channels causes synaptic
vesicles to fuse with the presynaptic plasma membrane and release the neurotransmitter
acetylcholine into the synaptic cleft. Acetylcholine diffuses across the cleft and
binds to muscle acetylcholine receptors, causing depolarization and an action potential
that travels throughout the length of the muscle cell triggering muscle contraction.
The release of neurotransmitter at the synapse involves the fusion of synaptic vesicles
with the neuronal plasma membrane and requires several proteins that act together
to form a synaptic fusion complex. These proteins, collectively called SNARE proteins,
include SNAP-25, syntaxin, and synaptobrevin. Homologs of these proteins are also
involved in membrane fusion in other aspects of vesicle trafficking. Synaptobrevin
(also called VAMP2) is localized at the synaptic vesicle membrane, while SNAP-25 and
syntaxin are associated with the plasma membrane. Calcium release causes the formation
of a complex, bringing the synaptic vesicle in close proximity with the plasma membrane
and allowing fusion of the membranes. Biological toxins often disrupt nervous function,
particularly the action of motor neurons. Botulinum toxin, synthesized by the bacteria
Clostridium botulinum, is one of the most potent toxins known and acts by blocking
neurotransmitter release at the neuromuscular junction. Botulinum toxin is a protein
composed of two subunits joined by a disulfide bond, a 100 kD heavy subunit and a
50 kD light subunit that is a protease. There are seven serotypes of botulinum with
distinct toxins. Tetanus toxin is similar in structure and in mechanism of action
to botulinum toxin. The toxins can be absorbed in the intestine to travel in the blood
to its site of action, at the neuromuscular junction. At the synapse botulinum toxin
binds to the presynaptic membrane, and large subunit mediates internalization into
the neuron through endocytosis. Once inside the neuron, the light chain is translocated
across the vesicular membrane to act as a protease on cytoplasmic substrates. The
targets of the toxin protease include the components of the synaptic fusion complex.
Tetanus toxin and botulinum B, D, F and G toxins degrade synaptobrevin, while botulinum
A, C and E toxins cleave SNAP-25. Syntaxin is also targeted by serotype C toxin. Destruction
of these proteins by botulinum toxin prevents vesicular fusion in response to action
potentials, blocking the release of acetylcholine. This blockade of communication
between the nervous system and skeletal muscle can cause paralysis and can lead to
death if the paralysis is severe enough to prevent breathing. In addition to acting
as a toxin during botulism infection, botulinum toxin is also now being used as a
pharmaceutical. Careful administration of very small doses of toxin can restrict its
action locally to reduce overactive muscles, such as those involved in twitching of
the eyes. Relaxing the muscles around the eyes can also reduce wrinkles in the eye
region, leading to cosmetic use of this potent bacterial toxin. The potency of botulinum
toxin has also caused concern that it could be used as a biological weapon, creating
interest in the identification of inhibitors of this toxin. (This definition may be
outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_botulinPathway;
Origin ID : C39007;
UMLS CUI : C1511277;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
