Molecular Pharmacology, Vol 20, 107-112, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

The Interaction of Ervatamine and Epiervatamine with the Action Potential Na⁺ Ionophore

¹ Centre de Biochimie du Centre National de la Recherche Scientifique (CNRS), Faculté des Sciences, Université de Nice, Parc Valrose, 06034 Nice Cedex, France, and Institut de Chimie des Substances Naturelles, CNRS, Département de Chimie Organique Biologique et Thérapeutique, 91190 Gif sur Yvette, France

The alkaloid ervatamine blocks the voltage-sensitive Na⁺ conductance. EC₅₀ for different cell lines and for synaptosomes range between 1-3 and 5-12 µM. The toxic compound also alters the K⁺ conductance, although less efficiently than the Na⁺ conductance. Epiervatamine, a structural analogue of ervatamine, is 4-8 times more potent than ervatamine. Dose-response curves for ervatamine and epiervatamine show that the compounds bind to a single class of binding sites. Competition experiments with a radiolabeled tetrodotoxin (TTX) derivative indicate that these binding sites are distinct from the TTX receptor site. Ervatamine and epiervatamine seem to inhibit the Na⁺ current (or Na⁺ flux) by acting on the channel-gating mechanism. ²²Na⁺ uptake measurements with neuroblastoma cells show that epiervatamine is a competitive inhibitor of the action of batrachotoxin, a well known specific activator of the Na⁺ channel. The dissociation constant of epiervatamine from its receptor site is 1.7 µM, very similar to that of batrachotoxin K_d = 1.3 µM from a receptor site which could then be the same as that for epiervatamine. Although ervatamine and epiervatamine, like TTX, can inhibit the action that sea anemone and scorpion toxins have on Na⁺ channels, none of them antagonize the binding of these radiolabeled polypeptide toxins to their own receptor sites on the gating system of the channel. A comparison has been made of the effects of ervatamine and epiervatamine on one hand, and yohimbine and tetracaine on the other hand. The mechanisms of action of yohimbine, ervatamine, and epiervatamine appear to be very similar. However, epiervatamine is 10 times more potent than yohimbine.

Note:
ACKNOWLEDGMENTS The authors are very grateful to M. T. Ravier, N. Alenda, and M. Valetti for expert assistance, and to Drs. A. Lombet and J. Barhanin for the synthesis of [³H]en-TTX, [¹²⁵I]ATX₁₁ and [¹²⁵I]ScTX₁₁.