[Mechanisms of action of botulinum toxins and neurotoxins].
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. BoNTs specifically inhibit vesicular neurotransmitter release. The cellular action of BoNTs can be depicted according to a multi-step model : The toxin's heavy chain mediates binding to specific receptors comprised of a ganglioside moiety and a vesicular protein (SV2 for BoNT type A, synaptotagmin for BoNT type B), followed by endocytotic internalisation of the BoNT/receptor complex. 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-synapto-brevin, 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 blockade of neurotransmitter exocytosis. Importantly, as the BoNT receptors and intracellular targets are present in all nerve terminals, the BoNTs are not specific for cholinergic transmission. Duration of their inhibitory action is mainly determined by the the life-time of the toxin's light chain in the cytosol. Sprouting of new nerve-endings, which are retracted when the poisoned nerve terminals have recovered full functionality, may lead to anticipated recovery of the poisoned nerve terminals.
Poulain
B
B
Centre National de la Recherche Scientifique associé à l'Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives UPR3212, Strasbourg. poulain@neurochem.u-strasbg.fr
Lonchamp
E
E
Jover
E
E
Popoff
M R
MR
Molgó
J
J
D001905:Botulinum Toxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003014:Clostridium botulinum / Q000378:metabolism; D003879:Dermatologic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009465:Neuromuscular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects
D003879:Dermatologic Agents; D009419:Nerve Tissue Proteins; D009465:Neuromuscular Agents; D008666:Metalloendopeptidases; D001905:Botulinum Toxins