Dolly_1990_J.Physiol.(Paris)_84_237

Reference

Title : Clues to the multi-phasic inhibitory action of botulinum neurotoxins on release of transmitters - Dolly_1990_J.Physiol.(Paris)_84_237
Author(s) : Dolly JO , Ashton AC , McInnes C , Wadsworth JD , Poulain B , Tauc L , Shone CC , Melling J
Ref : Journal de Physiologie (Paris) , 84 :237 , 1990
Abstract :

1. With the aim of gaining insight into the mechanism of Ca2(+)-dependent secretion, inhibition of transmitter release by botulinum neurotoxins or their fragments was studied at mammalian motor nerve terminals, cerebrocortical synaptosomes and PC-12 cells. 2. Relative to BoNT type A, the feeble neuromuscular paralytic activity of its two chains and the lack of activity observed with a proteolytic fragment, H2L (lacking H1, the C-terminal half of the heavy chain) highlight a requirement of the intact, disulphide-linked dichain protein for efficient targetting (binding/uptake) to peripheral cholinergic nerve endings. 3. In PC-12 cells, the renatured light chain alone proved equally potent as the whole toxin in reducing Ca2(+)-evoked noradrenaline release, when digitonin-permeabilization was used to overcome the uptake barrier. Treatment of BoNT A with 10 mM dithiothreitol, under non-denaturing conditions, was not very effective in reducing its inter-chain disulphide bond(s) and had little influence on the level of inhibition seen. 4. Altering the intra-synaptosomal concentrations of cyclic nucleotides (c-AMP, c-GMP) or protein kinase C activity failed to affect the reduction of Ca2(+)-dependent K(+)-stimulated noradrenaline release caused by BoNT A or B. On the other hand, raising the cytosolic Ca2+ concentration with the ionophore A23187 reversed the inhibitory effect of BoNT A to a greater extent than that of type B, revealing differences in their actions. 5. Whereas BoNT-induced decrease of Ca2(+)-dependent K(+)-evoked release of noradrenaline was unaffected by destruction of the actin-based cytoskeleton in synaptosomes with cytochalasin D, disassembly of microtubules with colchicine, nocodazole or griseofulvin antagonised the intracellular action of type B but not A. It is speculated that BoNT B blocks transmitter release by interfering with the proposed detachment of synaptic vesicles from microtubules. Establishing the precise involvement of tubulin in the toxin's action may provide a valuable clue to the mechanism of neurotransmitter release or its control.

PubMedSearch : Dolly_1990_J.Physiol.(Paris)_84_237
PubMedID: 1963641

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Citations formats

Dolly JO, Ashton AC, McInnes C, Wadsworth JD, Poulain B, Tauc L, Shone CC, Melling J (1990)
Clues to the multi-phasic inhibitory action of botulinum neurotoxins on release of transmitters
Journal de Physiologie (Paris) 84 :237

Dolly JO, Ashton AC, McInnes C, Wadsworth JD, Poulain B, Tauc L, Shone CC, Melling J (1990)
Journal de Physiologie (Paris) 84 :237