[Action mechanisms of botulinum neurotoxins and tetanus neurotoxins].
Tetanus (TeNT) neurotoxin and botulinum (BoNT, serotypes A-G) neurotoxins are di-chain bacterial proteins of MW-150 kDa which are also termed as clostridial neurotoxins. They are the only causative agents of two severe neuroparalytic diseases, namely tetanus and botulism. The peripheral muscle spasms which characterise tetanus are due to a blockade of inhibitory (GABAergic and glycinergic) synapses in the central nervous system leading to a motor neurones desinhibition. In contrast, botulism symptoms are only peripheral. They are consequent to a near irreversible and highly selective inhibition of acetyl-choline release at the motor nerve endings innervating skeletal muscles. During the past decade, the cellular and molecular modes of action of clostridial neurotoxins has been near completely elucidated. After a binding step of the neurotoxins to specific membrane acceptors located only on nerve terminals, BoNTs and TeNT are internalized into neurons. Inside their target neurones, the intracellularly active moiety (their light chain) is translocated from the endosomal compartment to the cytosol. The neurotoxins' light chains are zinc-dependent (endopeptidases which are specific for one among three synaptic proteins (VAMP/synaptobrevin, syntaxin or SNAP-25) implicated in neurotransmitter exocytosis. The presence of distinct targets for BoNTs and TeNT correlates well with the observed quantal alterations of neurotransmitter release which characterize certain toxin serotypes. In addition, evidence for a second, non-proteolytic, inhibitory mechanism of action has been provided recently. Most likely, this additional blocking action involves the activation of neurone transglutaminases. Due to their specific action on key proteins of the exocytosis apparatus, clostridial neurotoxins are now widely used as molecular tools to study exocytosis.
Deloye
F
F
Laboratoire de Neurobiologie Cellulaire et Moléculaire, UPR 9040 du CNRS, Gif-sur-Yvette.
Doussau
F
F
Poulain
B
B
D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology*; D001906:Botulism / Q000503:physiopathology; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000201:enzymology; D009498:Neurotoxins / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D013569:Synapses / Q000737:chemistry / Q000187:drug effects; D013742:Tetanus / Q000503:physiopathology; D013744:Tetanus Toxin / Q000494:pharmacology*; D011503:Transglutaminases / Q000187:drug effects / Q000378:metabolism
D009498:Neurotoxins; D018377:Neurotransmitter Agents; D013744:Tetanus Toxin; D011503:Transglutaminases; D001905:Botulinum Toxins