Modelling the activation, opening, inactivation and reopening of the voltage–gated sodium channel

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Abstract
A model of the voltage–gated sodium channel is put forward suggesting that the four S4 voltage–sensors behave as screw–helices making a series of discrete transitions that carry one elementary charge for each notch of the screw helix. After the channel has been activated by the first two steps R ⇌ P ⇌ A in all four domains, followed by a voltage–independent rearrangement, it is opened by a third cooperative step A ⇌ B in domains I, II and III in conjunction with hydration. Inactivation is a voltage–dependent process controlled by the third step A ⇌ I in sensor IVS4, and the closing of the channel is brought about its dehydration. From the inactivated steady state the channel may be reopened by a fourth step, I ⇌ C in sensor IVS4 and rehydration. The computed kinetics of the model are shown to conform closely with those observed experimentally.