Interactions of neurotoxins with the action potential NA + ionophore

Four neurotoxins that activate the action potential Na+ionophore of electrically excitable neuroblastoma cells interact with two distinct classes of sites, one specific for the alkaloids veratridine, batrachotoxin, and aconitine, and the second specific for scorpion toxin. Positive heterotropic cooperativity is observed between toxins bound at these two classes of sites. Tetrodotoxin, a specific inhibitor of the action potential Na+ current, inhibits activation by each of these toxins in a noncompetitive manner (KI=4-8 nM). These results suggest the existence of three functionally separable components of the action potential Na+ionophore: two regulatory components which bind activating neurotoxins and interact allosterically in controlling the activity of a third ion-transport component, which binds tetrodotoxin. The dissociation constant for scorpion toxin binding is increased 10-fold by depolarization of the cells with K+, suggesting that the scorpion toxin binding site is located on a voltage-sensitive regulatory component of the ionophore.