ABSTRACT
In the past decade tremendous strides have been made toward unraveling the molecular mechanisms of action of clostridial neurotoxins, in general, and tetanus toxin in particular. For almost 50 years tetanus toxin, a potent di-chain neurotoxin, has been known to block neurotransmitter release from the nerve terminal by interfering with some essential process controlling exocytosis (Mellanby and Green, 1981). The crucial finding leading to this sequence of studies was that intracellularly injected tetanus toxin inhibited exocytosis in bovine adrenal chromaffin cells (Penner et al., 1986). The authors “localized the secretion-blocking effects of the toxin to a fragment comprising the light chain covalently linked to part of the heavy chain, suggesting that this part of the molecule contains the active site.” This study was supported by experiments using permeabilized chromaffin cells in which various forms of tetanus toxin inhibited exocytosis (AhnertHilger et al., 1989, 1989a; Lazarovici et al., 1989). The next step was the discovery by Cesare Montecucco et al. that tetanus neurotoxin contains one atom of zinc bound to the light chain and coordinated via two histidine residues of a highly conserved zinc binding motif of zinc endopeptidase (Schiavo et al., 1992b) thereby, identifying tetanus toxin as a metalloendoprotease. These discoveries culminated in the findings that tetanus toxin substrates are synaptobrevin II (Schiavo et al., 1992a) and cellubrevin (McMahon et al., 1993), proteins likely to form the core of the neurotransmitter vesicle docking/fusion complex that is structurally and functionally conserved in regulated and constitutive exocytosis. Finally, using an elegant approach, the gene encoding the light chain of tetanus toxin was targeted to drosophila embryonic neurons, resulting in synaptobrevin elimination during embryonic development and abolition of synaptic transmission and
behavioral defects (Sweeney et al., 1995). These and other studies presented in this volume have provided deep insights into the molecular mechanisms of exocytosis and tetanus toxin action, focusing our attention on the role of synaptobrevins in secretory systems. However, another basic, consistent property of tetanus toxin, the interaction with polysialogangliosides and the possible neuronal effects of this molecular recognition have not received due attention and will be addressed in this chapter. Suggestions will be made, which, I hope, will contribute to a further understanding of the action of tetanus toxin on the nervous system.
