Voltage-sensor cycle fully described.

I on channels provide the most rapid way of communication between the cell interior and the external environment by exploiting the differences in electrolyte composition between the internal and external cellular milieu to transmit electrical and chemical signals (1). Voltage-gated ion channels in particular open and close in response to changes in the membrane electrical potential. Voltage-gated K and Na channels induce nerve impulses whereas voltagegated Ca channels initiate muscle contraction and other cellular processes (1). High-resolution X-ray crystallographic structures of some of these proteins have already been determined, showing that they are composed of four subunits, each consisting of six transmembrane segments (S1–S6) and forming two functionally linked, although structurally independent, domains (2–4). The ion conduction pore responsible for selectivity is formed by helices S5 and S6. This pore domain is surrounded by the loosely adherent segments, S1 to S4, which form the voltage sensor. S3 is actually composed of two helices referred as S3a and S3b. S3b forms with S4 a helix–turn–helix called the voltage-sensor paddle (3). The fourth transmembrane helix, S4, is the primary voltage-sensing unit. Four to seven positively charged amino acid spaced at intervals of three in the S4 helix and known as gating charges, and some negatively charged residues distributed in S1, S2, and S3, move in response to change of transmembrane voltage, activating upon membrane depolarization (positive inside relative to outside) and driving the opening of the channel. These sensors are arranged as nearly independent domains, with much of their surface surrounded by lipids even if direct exposure of S4 sensors to lipid is contrary to the classical expectation that the dielectric difference between the membrane hydrocarbon core and the aqueous solution presents an energetic penalty to burial of electric charges (5).