Clostridium Endocytosis

Acetylcholine release is inhibited by one of the most potent toxins, the botulims toxin produced by the anaerobic bacterium Clostridium botulinum. The toxin, lethal at 1 ng/kg in humans, enters the synapse by endocytosis at nonmyelinated synaptic membranes and produces muscle paralysis by blocking the active zone of the presynaptic membrane... 

Tetanus is characterised by a prolonged contraction of skeletal muscle fibres the neurotoxin responsible is from Clostridium tetani. The toxin initially binds to peripheral nerve terminals and is then transported within the axon and across synaptic junctions until it reaches the central nervous system (CNS). Here it attaches to ganghosides at the presynaptic inhibitory motor nerve endings and is taken up into the axon by endocytosis. The effect of the toxin is to block the release of inhibitory neurotransmitters (glycine and gamma-amino butyric acid), which are required to check the nervous impulse, leading to the generalised muscular spasms characteristic of tetanus. 

Simpson LL, Stiles BG, Zapeda HH et al. (1987) Molecular basis for the pathological actions of Clostridium perfringens lota toxin. In Infect. Immun. 55 118-22 Simpson LL (1989) The binary toxin produced by Clostridium botulinum enters cells by receptor-mediated endocytosis to exert its pharmacologic effects. In J. Pharmacol. Exp. Ther. 251 1223-8... 

Simpson LL (1989b) The binary toxin produced by Clostridium botulinum enters cells by receptor-mediated endocytosis to exert its pharmacologic effects. In J Pharmacol Exp Then 251 1223-8... 

Toxin B is an intracellularly acting cytotoxin and enters the cell via a receptor-mediated endocytosis pathway to reach the endosomes, from which the toxin is translocated to the cytoplasm (Florin and The-lestam, 1986 Henriques etal., 1987). Because of this specific mode of entry, the toxin concentration needed for intoxication of cells is low (lOOng/ml for about 4h). In contrast, Clostridium bofulinum exoenzyme C3 (23.5 kDa), which ADP-ribosylates the Rho subtype proteins RhoA, B and C only, enters the cells by a non-specific uptake process, possibly by pinocytosis. Therefore, C3 has to be applied in high concentrations (about 30 g/ml) for 24 h or longer. 

Botulinum neurotoxins (seven serotypes, A-G) are relatively large water soluble proteins (150 kDa) produced by the Clostridium botulinum. Each protein has two polypeptide chains (a 100 kDa heavy chain and a 50 kDa light chain) linked through a disulfide bond (Fig. 2). In the proposed mode of action of botulinum and tetanus neurotoxins (Simpson, 1986, 1989), the C-terminal half of the heavy chain binds to the nerve membrane leading to internalization of the neurotoxin in the nerve cell through endocytosis. Subsequently, the pH of the endosome is lowered causing the heavy chain to get integrated in the membrane... 

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