The chemical basis for electrical signaling

A highlight of the knowledge derived in large part from structural work on physical motions and chemical interactions involved in voltage sensing, pore opening, ion conductance and selectivity, and voltage-dependent inactivation mechanisms of the voltage-gated channels Na V and Ca V . Electrical signals generated by minute currents of ions moving across cell membranes are central to all rapid processes in biology. Initiation and propagation of electrical signals requires voltage-gated sodium (Na V ) and calcium (Ca V ) channels. These channels contain a tetramer of membrane-bound subunits or domains comprising a voltage sensor and a pore module. Voltage-dependent activation occurs as membrane depolarization drives outward movements of positive gating changes in the voltage sensor via a sliding-helix mechanism, which leads to a conformational change in the pore module that opens its intracellular activation gate. A unique negatively charged site in the selectivity filter conducts hydrated Na + or Ca 2+ rapidly and selectively. Ion conductance is terminated by voltage-dependent inactivation, which causes asymmetric pore collapse. This Review focuses on recent advances in structure and function of Na V and Ca V channels that expand our current understanding of the chemical basis for electrical signaling mechanisms conserved from bacteria to humans.