Inhibitors of Synaptic Vesicle Release: Botulinum and Tetanus Toxins

Synaptic Vesicle Release Overview

The brain is the headquarters of the central nervous system, playing a significant role in controlling and regulating human behavior and physiological processes, the functions of which principally depend on neurons, the basic units of the nervous system. Neural information is transmitted on neurons in the form of action potentials and between neurons (or among synapses) in the form of neurotransmitters. Generally, the neurotransmitters are released into the synaptic space and then act on the postsynaptic membrane, resulting in the next neuron being excitatory or inhibitory. The process that neurotransmitter in vesicles is released from presynaptic membrane to synaptic space by exocytosis is known as synaptic vesicle release.

The synaptic vesicle release is regulated by exocytosis in a voltage-dependent calcium channel manner. Molecules involved in the formation of synaptic vesicles, the fusion of vesicles to presynaptic membrane, the function of the calcium channel are closely related to synaptic vesicle release. While several neurotoxins or other inhibitors can restrain the synaptic vesicle release by affecting these biological processes.

Synaptic Vesicle Release Inhibitors

• Botulinum Toxin

Clostridium botulinum (C. botulinum), a Gram-positive, anaerobic, and spore-forming bacterium in the Clostridium genus, is characterized by the ability to produce botulinum exotoxins. Botulinum toxin is one of the most poisonous neurotoxins, comprising different 8 types (A, B, C1, C2, D, E, F, and G). Botulinum toxin A is a single polypeptide chain consisting of two disulfide-linked chains (a heavy chain and a light chain), which is the most potent neurotoxin. Although it was identified as neurotoxins, several botulinum-toxin drugs have been approved for clinical disease treatment.

All botulinum toxins act as neurotoxins by interfering with the transmission of neurotransmitters (mainly acetylcholine) by preventing the neurotransmitter vesicle release. During vesicle recycling, the botulinum toxin heavy chain can selectively and irreversibly bind to the presynaptic receptors. When the botulinum toxin-receptor complex is endocytosed into the neuron, the disulfide bond is cleaved through intravesical acidification, releasing the botulinum toxin into the cell. The botulinum toxin light chain in the cytoplasm can bind to and cleave vesicle or synaptosomal associated proteins to prevent neurotransmitter acetylcholine vesicles fuse with the presynaptic membrane, thereby blocking acetylcholine release. Recently, the neurotoxicity of botulinum toxin has been developed and exploited for treatment of a number of neurological conditions. Botulinum neurotoxin type A was approved by the Food and Drug Administration for treating migraines in 2010 and for bladder hyperactivity in 2011.

Fig.1 Botulinum neurotoxin blocking acetylcholine release. (Peng Chen, 2012)

• Tetanus Toxin

Tetanus toxin, also known as tetanospasmin, is another kind of neurotoxin second only to the botulinum toxin, which is produced by the bacterium Clostridium tetani. Like botulinum neurotoxin, tetanus toxin also is a single polypeptide with a heavy chain and a light chain connected by a disulfide bond. The mechanism of tetanus toxin in synaptic vesicle release inhibition is different from botulinum neurotoxins.

Initially, tetanus toxin binds to the presynaptic terminals of the neuromuscular junction, and then is transported across synapses to the spinal cord, where tetanus toxin is finally transferred into inhibitory presynaptic terminals, such as GABAergic neurons and glycinergic neurons. Tetanus toxin in neuron reacts with and cleave the vesicle-associated membrane protein or synaptobrevin to prevent the release of inhibitory neurotransmitters (e.g., γ-aminobutyric acid and glycine), thereby enhancing the excitability of the motor neurons and leading to muscle hyperexcitability.

Fig.2 Tetanus toxin uptake and action. (Fishman, 2009)

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References

1. Peng Chen, Z.; et al. Emerging Opportunities for Serotypes of Botulinum Neurotoxins. Toxins (Basel). 2012, 4(11): 1196-1222.
2. Fishman, P.S. Tetanus Toxin. In: Botulinum Toxin. Therapeutic Clinical Practice and Science.  2009, pp: 406-424, 424.e1.