How botulinum and tetanus neurotoxins block neurotransmitter release.
Botulinum neurotoxins (BoNT, serotypes A-G) and tetanus neurotoxin (TeNT) are bacterial proteins that comprise a light chain (M(r) approximately 50) disulfide linked to a heavy chain (M(r) approximately 100). By inhibiting neurotransmitter release at distinct synapses, these toxins cause two severe neuroparalytic diseases, tetanus and botulism. The cellular and molecular modes of action of these toxins have almost been deciphered. After binding to specific membrane acceptors, BoNTs and TeNT are internalized via endocytosis into nerve terminals. Subsequently, their light chain (a zinc-dependent endopeptidase) is translocated into the cytosolic compartment where it cleaves one of three essential proteins involved in the exocytotic machinery: vesicle associated membrane protein (also termed synaptobrevin), syntaxin, and synaptosomal associated protein of 25 kDa. The aim of this review is to explain how the proteolytic attack at specific sites of the targets for BoNTs and TeNT induces perturbations of the fusogenic SNARE complex dynamics and how these alterations can account for the inhibition of spontaneous and evoked quantal neurotransmitter release by the neurotoxins.
Humeau
Y
Y
Laboratoire de Neurobiologie Cellulaire, UPR 9009 du CNRS, Centre de Neurochimie, 5, rue Blaise-Pascal, 67084 cedex, Strasbourg, France.
Doussau
F
F
Grant
N J
NJ
Poulain
B
B
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D013744:Tetanus Toxin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D013744:Tetanus Toxin; D008666:Metalloendopeptidases; D001905:Botulinum Toxins