A new look at the mechanism of activation and inactivation of voltage-gated ion channels.

Studies on the kinetics of activation and inactivation of the sodium channels of the squid giant axon, on the sodium gating current, and on the properties of the non-inactivating steady-state current, are briefly reviewed. Taken in conjunction with recent evidence on the structure of voltage-gated ion channels, they have led to the development of a series-parallel model of the sodium channel that can be regarded as a modernized version of the Hodgkin-Huxley model, with some novel features. It is suggested that activation results from conformational changes brought about by the four S4 voltage sensors operating in parallel, each of which makes two discrete steps to reach the fully activated state of the channel. There follows a voltage-independent hydration step, and the channel is ready to open. Inactivation is a potential-dependent process involving a third transition of voltage sensor S4d alone, which, rather than bringing a ball and chain blocking group into position to close the channels, serves to switch the system so that it passes from an initial activated mode, in which there is a high probability of arriving at an open state with a brief latency, to a second steady-state mode, in which the probability of opening is very much lower.