Molecular Pharmacology, Vol 17, 172-179, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Nereistoxin Interaction with the Acetylcholine Receptor-Ionic Channel Complex

¹ Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201

The effect of nereistoxin (NTX) was studied, by electrophysiological methods on neuromuscular transmission in frog sartorius and rat diaphragm muscles, and by biochemical methods on binding of ligands to the acetylcholine (ACh) receptor and its ionic channel in membranes from Torpedo electroplax. NTX blocked the indirectly elicited twitch tension but not the directly elicited ones, and did not affect action potential, quantal content and frequency of the spontaneous miniature endplate potentials. The postsynaptic inhibition by NTX was evident from the reduction it caused in the amplitudes of the endplate potential and endplate current as well as the extrajunctional ACh sensitivity of denervated rat soleus muscle, and its inhibition of binding of [³H]ACh and [¹²⁵I]-bungarotoxin to Torpedo ACh receptors. In addition, NTX caused initial postsynaptic depolarization and potentiation of the indirectly elicited twitch tension. Although NTX by itself activated receptor-induced ²²Na influx in Torpedo microsacs to a small degree, it also inhibited the carbamylcholine-activated ²²Na influx. Since NTX did not inhibit binding of [³H]perhydrohistrionicotoxin to Torpedo membranes and did not alter the linearity of the current voltage relationship, nor the time course of endplate current in frog sartorius muscle, we suggested that its inhibition of neuromuscular transmission was due to its inhibition of the ACh-receptor sites and not the ionic channel sites. Also, NTX acted as a partial agonist since it could activate the ACh receptor although its major action was that of an antagonist.

Note:
ACKNOWLEDGMENTS We are grateful to Dr. M. Sakai of Takeda Chemical Industries, Kyoto, Japan, for kindly donating the nereistoxin used in the present study and to Drs. B. Witkop and J. Daly of the National Institutes of Health for kindly providing us with [³H]perhydrohistrionicotoxin. We are most indebted to Ms. Mabel Alice Zelle for the computer analysis.

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