Interaction of pyrethroids with the Na+ channel in mammalian neuronal cells in culture.

The interaction of a series of pyrethroids with the Na+ channel of mouse neuroblastoma cells has been followed using both an electrophysiological and a 22Na+ influx approach. By themselves, pyrethroids do not stimulate 22Na+ entry through the Na+ channel (or the stimulation they give is too small to be analyzed). However, they stimulate 22Na+ entry when used in conjunction with other toxins specific for the gating system of the channel. These include batrachotoxin, veratridine, dihydrograyanotoxin II or polypeptide toxins like sea anemone and scorpion toxins. This stimulatory effect is fully inhibited by tetrodotoxin with a dissociation constant of 1.6 nM for the tetrodotoxin-receptor complex. Half-maximum saturation of the pyrethroid receptor on the Na+ channel is observed in the micromolar range for the most active pyrethroids, Decis and RU 15525. The synergism observed between the effect of pyrethroids on 22Na+ influx on the one hand, and the effects of sea anemone toxin II, Androctonus scorpion toxin II, batrachotoxin, veratridine and dihydrograyanotoxin II on the other, indicates that the binding component for pyrethroids on the Na+ channel is distinct from the other toxin receptors. It is also distinct from the tetrodotoxin receptor. Some of the pyrethroids used in this study bind to the Na+ channel but are unable to stimulate 22Na+ entry. These inactive compounds behave as are unable to stimulate 22Na+ entry. These inactive compounds behave as antagonists of the active pyrethroids. An electrophysiological approach has shown that pyrethroids by themselves are active on the Na+ channel of mammalian neurones, and essentially confirm the conclusions made from 22Na+ flux measurements. Pyrethroids are also active on C9 cells in which Na+ channels are 'silent', that is, not activatable by electrical stimulation. Pyrethroids chemically activate the silent Na+ channel in a manner similar to that with veratridine, batrachotoxin, or polypeptide toxins, which are known to slow down the inactivation process of a functional Na+ channel.