Light-activated drug confirms a mechanism of ion channel blockade

Abstract

A VARIETY of mechanisms underlie the pharmacological blockade of membrane excitability. Some drugs seem to reduce the frequency at which ion channels open; a good example is the effect of curare on acetylcholine receptor channels at normal resting potentials. Another sort of mechanism may account for the action of many local anaesthetics and related drugs containing charged ammonium groups. It is postulated that such molecules block transmembrane currents as they bind to sites within open ion channels, much like a plug in a drain, with the important difference that the events occur on a millisecond time scale. This model, which we shall call ‘open-channel blockade’, was first applied to the effect of internal tetraethylammonium ions on K⁺ channels in squid axon¹ and more recently to similar actions of local anaesthetics on acetylcholine receptor channels^2–4 and on electrically excitable Na⁺ channels⁵. (Curare seems to exert an additional open-channel blockade at high negative potentials^6,7.) The concept of open-channel blockade would receive direct experimental support from the demonstration that the blockade is exerted even if the blocking molecule is not bound to the channel (or indeed is not present at all) until after the channel opens. Such a demonstration is made possible by a drug that (1) blocks acetylcholine receptor channels in Electrophorus electroplaque, and (2) is created, in less than a millisecond, by a flash of light.