Gating in sodium channels of nerve.

Abstract

During the period 1937-1952 the study of electrical excitability mechanisms in axons matured from discoveries of membrane impedance changes to a complete kinetic description of ionic permeability changes in the squid giant axon (35). There followed a period of relative stagnation while the results on squid were rechecked and new voltage clamp methods were developed for other excitable systems. Then in the 1960s a new movement developed whose philosophy underlies the substantial activity and rate of progress characteristic of the field today. The new movement may be traced to the discovery of the specific blocking action of tetrodotoxin (TTX). TTX was shown to block the transient Na+ permeability of axon membranes with no effects on K+ permeability (47, 52, 53), and it was concluded that Na+ and K+ permeability are mediated by separate and discrete sites, now called Na channels and K channels. Very soon, techniques were developed to count the number ofTTX binding sites and hence the number of Na channels. These events finally replaced the idea of a homogeneous membrane endowed with diffuse ionic permeability by the idea of discrete molecular pores, the ionic channels. Arguments for molecular pores have been reviewed (3, 21, 28, 65, 66). The new molecular viewpoint has fostered efforts to count channels, to measure the permeability of single open channels, to measure their pore size and internal topography, to modify them chemically, and even to isolate them. Conceptually the channel is considered to have two fundamental properties: excitability and permea­ bility. Excitability means the ability to react to changes in the membrane potential and is loosely attributed to an electric field sensor coupled to gates that open or close the channel. Permeability includes the ability to let ions cross the membrane and the ability to discriminate among different ionic species. Permeability is presumed to be explainable in terms of the morphology and chemical nature of the pore revealed when the gates of the channel are open. Recent advances in explaining ionic permeability have just been reviewed (3, 21, 31, 32, 65); therefore this review turns