On molecular steps that activate a voltage sensitive ion channel at critical depolarization.

At high transmembrane electric field, a voltage sensitive ion channel is an insulator; when the field is critically reduced, it becomes a conductor of selected ions. The Channel Activation by Electrostatic Repulsion (CAbER) hypothesis proposes that an ordered polarization field of induced dipoles at the high electric field magnitude of the excitable state is overcome by thermal disorder at a critical depolarization. Increased repulsions between positive charges in the S4 segments cause an allosteric transition in which these segments expand and separate in a chiral proteinquake. The increased space allows the P segments to refold and the ion-semiconducting S5 and S6 segments to relax and expand outward in a breathing mode. Stripped permeant ions enter widened hydrogen bonds in the core helices of these segments. Driven by concentration differences and the electric field, the ions hop along transient pathways across the channel, appearing as fractal, stochastic bursts of single-channel currents. To support order amid thermal fluctuations, an object must be of a minimum size. The critical role of an ion channel's size suggests that the evolution of Metazoa became possible only after its DNA had grown enough to code for proteins larger than the correlation length. [Display omitted] • Branched sidechains are the link between depolarization and S4 movements. • Increased repulsions between positive charges drive the S4 segments apart. • As the pore-forming domain expands, its hydrogen bonds widen to become ion sites. • Permeant ions form fractal, stochastic bursts of current across the membrane. • Evolutionary gene doubling gave rise to large ordered phases of animal ion channels. [ABSTRACT FROM AUTHOR]