Clostridial neurotoxins release

Neurotoxins, such as the clostridial neurotoxins responsible for tetanus and botulism. These are metallo-proteases that enter nerve cells and block neurotransmitter release via zinc-dependent cleavage of protein components of the neuroexocytosis apparatus. 

The extreme toxicity of clostridial neurotoxins (CNTs) derives from their absolute neurospecificity as well as from catalytic activity. TeTx and BoNTs bind specifically to the neuromuscular junction (NMJ) of motor neurons. The identity of the receptor(s) on the presynaptic membrane is unknown, but their extreme toxicity suggests that the binding affinity to the cognate receptor must be very high. The receptor-bound toxin is internalized at the presynaptic membrane of the NMJ and gains access to the neuronal cytosol. Here it blocks the release of acetylcholine (ACh), causing a flaccid paralysis (Simpson,... 

Fig. 3. Specificity and sites of cleavage of the clostridial neurotoxins. VAMP is bound to the SSV membrane through a single transmembrane domain (black box), with the majority of the protein exposed to the cytoplasm. In addition, VAMP contains an amino-terminal domain rich in proline (hatched box). SNAP-25 and syn-taxin are bound to the target membrane via palmitoylation (SNAP-25) or via a single transmembrane domain (syntaxin). TeTx and BoNT/B, D, F or G act on the conserved central portion of VAMP and release its amino-terminal part into the cytosol. The sequences indicate the peptide bonds cleaved by CNTs on rat VAMP-1 and VAMP-2. BoNT/A and E cleave SNAP-25 at the carboxyl terminus, with the release of nine and twenty-six residues peptides respectively. BoNT/C also cleaves SNAP-25 at the carboxy-terminus, and cleaves syntaxin at a single site near the cytosolic membrane surface. The action of TeTx and BoNT/B, C, D, F and G causes the release of a large portion of the cytosolic domain of VAMP and syntaxin. Conversely, only a small segment of SNAP-25 is released by the selective proteolysis of BoNT/A, C and E...

Fig. 2. Schematic drawing that summarizes the procedure for monitoring the blockade of neurotransmitter release from brain synaptosomes, followed by immu-noblot analysis to detect specific proteolytic activity of clostridial neurotoxins on poisoned synaptosomes...

Poulain B, Molgo J and Thesleff S (1995). Quantal neurotransmitter release and the clostridial neurotoxins targets. In Montecucco C (ed.) Clostridial Neurotoxins. Springer Verlag, Berhn. 

Tetanus is a disease caused by the release of neurotoxins from the anaerobic, spore-forming rod Clostridium tetani. The clostridial protein, tetanus toxin, possesses a protease activity which selectively degrades the pre-synaptic vesicle protein synaptobrevin, resulting in a block of glycine and y-aminobutyric acid (GABA) release from presynaptic terminals. Consistent with the loss of neurogenic motor inhibition, symptoms of tetanus include muscular rigidity and hyperreflexia. The clinical course is characterized by increased muscle tone and spasms, which first affect the masseter muscle and the muscles of the throat, neck and shoulders. Death occurs by respiratory failure or heart failure. 

---