MOLECULAR MECHANISM OF ACTION OF TETANUS TOXIN AND BOTULINUM NEUROTOXINS

Tetanus toxin and botulinum neurotoxins are di-chain proteins of 150 k D molecular weight. They are produced by bacteria of the Clostridium g enus. These toxins act on the nervous system by inhibiting neurotransm itter release (glycine and GABA in the case of tetanus toxin; acetylch oline in the case of botulinum neurotoxins) thus inducing the spastic or flacid paralysis that characterizes tetanus and botulism, respectiv ely. Their cellular mechanism of action involves three main steps, nam ely binding to the neurone membrane, internalization and intracellular blockade of the release mechanism for neurotransmitters. Membrane acc epters for these toxins are not yet fully identified; they would consi st of membrane gangliosides and proteins. The internalization step wou ld be achieved by endocytosis. Recent findings show that both binding and internalization are mediated only by the heavy chain of the toxins whereas the intracellular blockade of neurotransmitter release involv es their light chain alone. The light chain has been identified as a z inc metalloprotease and its substrates would be proteins involved in t he neurotransmitter release mechanism. The target of tetanus toxin and of botulinum neurotoxin type B is VAMP/synaptobrevin, a membrane prot ein of the synaptic vesicles of nerve cell terminals.