[Mode of action of botulinum neurotoxin: pathological, cellular and molecular aspect].
Several bacteria of the Clostridium genus (C. botulinum) produce 150 kDa di-chainal protein toxins referred as botulinum neurotoxins or BoNTs. They associate with non-toxic companion proteins and form a complex termed botulinum toxin or BoTx. The latter is used in clinic for therapeutic purpose. BoNTs affect cholinergic nerve terminals in periphery where they block acetylcholine release, thereby causing dysautonomia and motorparalysis (i.e. botulism). The cellular action of BoNTs can be depicted according to a three steps model: binding, internalisation and intraneuronal action. The toxins heavy chain mediates binding to specific receptors followed by endocytotic internalisation of BoNT/receptor complex. BoNT receptors may comprise gangliosides and synaptic vesicle-associated proteins as synaptotagmins. Vesicle recycling induces BoNT internalisation. Upon acidification of vesicles, the light chain of the neurotoxin is translocated into the cytosol. Here, this zinc-endopeptidase cleaves one or two among three synaptic proteins (VAMP-synaptobrevin, SNAP25, and syntaxin). As the three protein targets of BoNT play major role in fusion of synaptic vesicles at the release sites, their cleavage is followed by blockage of neurotransmitter exocytosis. The duration of the paralytic effect of the BoNTs is determined by 1) the turnover of their protein target; 2) the time-life of the toxin light chain in the cytosol, and 3) the sprouting of new nerve-endings that are retracted when the poisoned nerve terminal had recovered its full functionality.
Poulain
B
B
Neurotransmission et sécrétion neuroendocrine, UPR 2356 du CNRS, IFR 37 des neurosciences, 5, rue Blaise-Pascal, 67084 Strasbourg cedex, France. poulain@neurochem.u-strasbg.fr
Humeau
Y
Y
D018726:Anti-Dyskinesia Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001342:Autonomic Nervous System Diseases / Q000188:drug therapy; D001905:Botulinum Toxins / Q000493:pharmacokinetics / Q000494:pharmacology*; D003014:Clostridium botulinum / Q000472:pathogenicity; D003600:Cytosol; D006801:Humans; D015394:Molecular Structure
D018726:Anti-Dyskinesia Agents; D001905:Botulinum Toxins