Exocytosis in neurons — Unraveling the molecular steps

Abstract

Botulinum (BoNT, serotypes A-G) and tetanus (TeNT) neurotoxins are di-chain bacterial proteins. They are also known under the generic term of clostridial neurotoxins. They are the causative agents of two severe neuroparalytic diseases, namely boutlism and tetanus. Boutlism is characterized by a near irreversible and selective inhibition of quantal acetylcholine release at the skeletal neuromuscular junctions. Tetanus is the result of a blockade of inhibitory synapses in the central nervous system. The cholinergic specificity of BoNTs allows to use these potent neurotoxins as pharmcological agents to induce a chemical denervation of muscle. The effect is exploited to better understand the trophic interrlations that exist between motor nerve terminals and muscle fibres and, in the clinic, to treat a number of disabling abnormal postures or movements such as dystonia and strabismus. The cellular and molecular modes of action of clostridial neurotoxins have been elucidated. After a binding step at specific membrance acceptors located only on nerve terminals, BoNTs and TeNT are internalized into neurons. Then, their intercellularly active moiety is translocated from the endosomal compartment to the cytosol. The intracellular inhibition of neurotransmitter release produced by BoNTs or TeNT involves their light chains and consists in the selective proteolysis of one among three synaptic proteins viz VAMP/synaptobrevin, syntaxin or SNAP-25. These different actions correlate with differneces in the quantal alternation of acetycholine release which characterize certains toxin serotypes. Thus, attempts at deciphering the multiple mode of action of BoNTs and TeNT gave insights into the molecular physiology of the synapses.