The Search Is on for the Voltage Sensor-to-gate Coupling

Hodgkin and Huxley (1952) demonstrated the presence of voltage-activated sodium (Na ) and potassium (K ) permeabilities in the squid giant axon. Ever since then, biophysicists have tried to understand how voltage activates the ionic pathways responsible for the action potential. Hodgkin and Huxley (1952) concluded that there had to be charges or charge dipoles in the membrane that move in response to changes in the voltage across the membrane, turning the Na and K permeabilities on and off. We now know that Na and K ions go through voltage-activated Na and K channels. These voltage-activated ion channels are composed of: (a) a pore-forming domain that contains the ion permeation pathway and the gates that control the flow of ions, (b) a voltage-sensing domain that contains the voltage sensor, and (c) a coupling mechanism that links the voltage sensor to the gates in the pore (Fig. 1). We have come a long way in our understanding of how ion channels work since Hodgkin and Huxley’s first voltage-clamp experiments. However, we still do not fully understand the molecular mechanism of how changes in voltage open and close these channels, and, we know even less about the coupling mechanism between the voltage sensors and the gates. In this Perspective, I give my view of the molecular mechanism of gating in voltage-activated K (Kv) channels and closely related ion channels (both voltage-gated and voltageindependent ion channels).