Abstract
Neurotoxins which activate voltage-sensitive sodium channels cause a 10-fold increase in the initial rate of 22Na+ uptake in synaptic nerve-ending particles (synaptosomes). Batrachotoxin is a full agonist in activating synaptosomal sodium channels, whereas veratridine and aconitine are partial agonists acting at the same receptor site. The 22Na+ uptake induced by alkaloid toxins is completely blocked by tetrodotoxin and saxitoxin. The Ki for saxitoxin (6 nM) is identical with the Kd for 3H-labeled saxitoxin binding to sodium channels in synaptosomes. The polypeptides scorpion toxin, Anemonia sulcata toxin II, and Anthopleurin A enhance activation of sodium channels by alkaloid toxins, reducing the K0.5 for all alkaloid toxins and increasing the fraction of sodium channels activated by the partial agonists. Scorpion toxin and A. sulcata toxin II are full agonists in this respect, whereas Anthopleurin A is a partial agonist. The three polypeptide toxins bind to a common receptor site, and the concentration dependence of binding and activation of 22Na+ influx are closely correlated. Alkaloid toxins markedly enhance 125I-labeled scorpion toxin binding to its receptor site, demonstrating bidirectional allosteric coupling between the receptor sites for polypeptide and alkaloid toxins. The concentration-effect curves for alkaloid toxin enhancement of 125I-labeled scorpion toxin binding and 22Na+ uptake are closely correlated. Depolarization enhances the effect of alkaloid toxins on 125I-labeled scorpion toxin binding but does not alter the effect of saturating concentrations of scorpion toxin on batrachotoxin activation. In depolarized synaptosomes, this allosteric coupling between the alkaloid toxin and polypeptide toxin receptor sites is quantitatively fit by a model which assumes that both the alkaloid and polypeptide toxins act by binding selectively to active states of sodium channels.
ACKNOWLEDGMENTS We thank Dr. T. R. Norton for providing Anthopleurin A, Dr. L. Beress for providing sea anemone toxin II, and Drs. J. Daly and B. Witkop for providing batrachotoxin.
- Copyright © 1981 by The American Society for Pharmacology and Experimental Therapeutics
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