Although the molecular mechanisms of both botulinum and tetanus neurotoxins are highly homologous, each one’s resulting symptoms are rather different. Both toxins are produced by bacteria of the genus Clostridium and are composed of a heavy (H) and a light (L) chain connected by a disulfide bond that act as binding and active subunits, respectively. Evidence has suggested that botulinum (BoNT) and tetanus (TeNT) toxins require at least two cellular receptors, many of which are presently unknown. It is believed that all serotypes of BoNT as well as TeNT will bind ganglioside lipids such as GM1, GT, and GDb1, albeit with low affinity. The idea behind this is that low-affinity binding to gangliosides allows for localization of the toxins at the neuronal surface, after which they may be internalized into a synaptic vesicle. The process of internalization would then require a second receptor with a higher affinity for binding the toxin. Studies have identified a few protein receptors, including the luminal domain of SV2 for BoNT serotype A, the luminal domain of synaptotagmin for BoNT serotypes B and G, as well as a GPI-anchored protein Thy-1 for TeNT. It is believed that TeNT has even more hitherto undiscovered receptors since its mechanism involves extra trafficking. Regardless, the notion of multiple receptors for these two types of toxins would give support for the neurospecificity seen in each case.
Both tetanus and botulinum toxins are endocytosed into synaptic vesicles according to their high-affinity binding to synaptic vesicle proteins. While different serotypes of BoNT cleave various SNARE proteins involved in binding and docking of vesicles with the synaptic membrane, for the purposes of comparison, serotype B (BoNT/B) will be discussed exclusively in relation to the enzymatic activity of tetanus toxin. After TeNT and BoNT/B bind the synaptic membrane and are subsequently internalized, the light chain will be pushed onto the vesicular surface with the help of the heavy chain’s translocation domain. Once exposed, the light chain causes proteolytic cleavage of VAMP/synaptobrevin, which is a v-SNARE. Although both neurotoxins cleave at the same amino acid bond in VAMP/synaptobrevin, the resulting symptoms are actually opposite one another. Whereas botulinum toxin induces flaccid paralysis in muscles, tetanus toxin’s effect is a spastic paralysis. The reason for these starkly opposing symptoms is ultimately attributed to the specific location at which the toxins are shown to act.
The effects of BoNT are localized at the presynaptic cleft of a neuromuscular junction. At this location, the toxin has been taken into synaptic vesicles and it cleaves VAMP; as a consequence, the toxin blocks other vesicles from the ability to bind to corresponding t-SNARES on the synaptic membrane, followed by fusion and release acetylcholine neurotransmitter via exocytosis. Thus, motor signals that are sent along neurons to affect muscle fibers are completely blocked due to the inhibition of acetylcholine release at the neuromuscular junction and the intoxicated animal suffers a flaccid muscle paralysis. While tetanus toxin cleaves the same v-SNARE protein, its action is seen elsewhere in the neuron. Interestingly, whereas BoNT is largely focused at the presynaptic membrane of the neuromuscular junction, TeNT is retrogradely trafficked to the cell body of the motor neuron following its internalization into a vesicle. Reaching the cell body, tetanus toxin is delivered into the presynaptic terminal of inhibitory interneurons that normally send a signal to keep muscle tissues from contracting. At this point, TeNT executes its action of VAMP cleavage, thereby blocking the release of inhibitory neurotransmitter much like BoNT does to stimulatory signals at the neuromuscular junction. The result of this blockage of inhibitory input into the motor neuron leads to excessive activity, wherein stimulatory neurotransmitter is released further downstream at the neuromuscular junction without an opposing signal to control it, and thus a spastic muscle paralysis associated with tetanus toxin ensues.
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