Long-range interactions, voltage sensitivity, and ion conduction in S4 segments of excitable channels

Forces acting on the S4 segments of the channel, the voltage-sensing structures, are analyzed. The conformational change in the Na channel is modeled as a helix-coil transition in the four S4 segments, coupled to the membrane voltage by electrical forces. In the model, repulsions between like charges make the S4 segment unstable, but field-dependent forces hold it in an alpha-helix configuration at resting potential. At threshold depolarization, the S4 helices cooperatively expand into random coils, breaking the hydrogen bonds connecting adjacent loops of the alpha helices. Exposed electron pairs left on the carbonyl oxygens constitute sites at which cations can bind selectively. The first hydrogen bond to break is at the channel exterior, then the second breaks, and so on in a zipper-like motion along the entire segment. The Na+ ions hop from one site to the next until all H bonds are broken and all sites are filled with ions. This completes the pathway over which the permeant ions move through the channel, driven by the electrochemical potential difference across the membrane. This microscopic mechanism is consistent with the thermodynamic explanation of ion-channel gating previously formulated as the ferroelectric-superionic transition hypothesis.