Further analysis of the mechanisms of action of batrachotoxin on the membrane of myelinated nerve

Abstract

This paper summarizes the investigations of the mode of action of batrachotoxin on frog myelinated nerve fibres. Batrachotoxin (10 −7−10 −5 m) alters a certain fraction of the sodium channels in the node of Ranvier so that the modified channels lose inactivation, and open and close with exponential kinetics. Batrachotoxin shifts the sodium activation by 50 mV to more negative voltages and increases the maximum time constant of activation by a factor of 10. The permeability sequence of the modified channels is as follows: NH 4 (1.4); Tl (1.3); Li (1.0); Na (1.0); K (0.4); guanidinium (0.4); Ca (0.4); Rb (0.25); Cs (0.15); methylammonium (0.10). The deviations of the ionic currents carried by tallium or guanidinium ions in the modified Na channels from the values predicted by the independence principle were significantly smaller than that for non-modified Na channels. Stimulation of the node of Ranvier with voltage pulses considerably accelerates the modification of Na channels providing the following two conditions are met: (i) the Na channels are not inactivated at the holding potential and (ii) the pulses are large enough to open them. Dose-response relations for batrachotoxin-induced modification show that one batrachotoxin molecule modifies one Na channel, the dissociation constant being 1000 n m. The receptor for batrachotoxin is considered to be linked allosterically to all principle subunits of the Na channel: the voltage sensor, the gates, and the selectivity filter. The opening of sodium channels seems to be a prerequisite stage for the modification induced by batrachotoxin. The comparison of the activation of intact and modified Na channels does not favour the traditional view that the gating mechanism of the Na channel is composed of several independent molecular subunits. The effect of batrachotoxin on the selectivity of Na channels is likely to be due to widening of the selectivity filter resulting in a smaller degree of dehydration of ions passing through the Na channel and smoothing the energy profile for ion-channel interaction. The similarity of the effects of batrachotoxin and another potent alkaloid, aconitine, are pointed out.