Inhibition by Botulinum Toxin of Acetylcholine Release from Synaptosomes: Latency of Action and the Role of Gangliosides |
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Authors: | S Wonnacott |
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Institution: | Department of Biochemistry, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF U.K. |
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Abstract: | Abstract: Crude and crystalline botulinum toxin type A have been compared for their ability to inhibit 14C]ACh release from synaptosomes preloaded with 14C]choline. The toxin preparations exhibited similar dose-response curves, with maximal inhibition at 105 mouse LD50/ml after 60 min preincubation. The time course for the inhibitory action of the toxin showed that inhibition develops almost linearly over this time period. However, free toxin could be removed from the synaptosome suspension after 15 min without altering the subsequent development of inhibition of 14C]ACh release, which suggests that the toxin is rapidly fixed by synaptosomes and that fixation alone cannot account for the latency of its action. Incorporation of gangliosides into synaptosomes by prior preincubation failed to increase the potency of the toxin, which implies that gangliosides do not serve as the membrane receptor for the toxin. Treatment of botulinum toxin with dithiothreitol greatly diminished its ability to inhibit 14C]ACh release and it is suggested that botulinum toxin may be analogous to other bacterial toxins in its structure and mode of action. |
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