Contributions of the membrane dipole potential to the function of voltage-gated cation channels and modulation by small molecule potentiators.

The membrane dipole potential (Ψd) constitutes one of three electrical potentials generated by cell membranes. Ψd arises from the unfavorable parallel alignment of phospholipid and water dipoles, and varies in magnitude both longitudinally and laterally across the bilayer according to membrane composition and phospholipid packing density. In this work, we propose that dynamic counter-balancing between Ψd and the transmembrane potential (ΔΨm) governs the conformational state transitions of voltage-gated ion channels. Ψd consists of 1) static outer, and dynamic inner leaflet components (Ψd(extra) and Ψd(intra), respectively); and 2) a transmembrane component (ΔΨd(inner-outer)), ariing from differences in intra- and extracellular leaflet composition. Ψd(intra), which transitions between high and low energy states (Ψd(intra, high) and Ψd(intra, low)) as a function of channel conformation, is transduced by the pore domain. ΔΨd(inner-outer) is transduced by the voltage-sensing (VS) domain in summation with ΔΨm. Potentiation of voltage-gated ion channels is of interest for the treatment of cardiac, neuronal, and other disorders arising from inherited/acquired ion channel dysfunction. Potentiators are widely believed to alter the rates and voltage-dependencies of channel gating transitions by binding to pockets in the membrane-facing and other regions of ion channel targets. Here, we propose that potentiators alter Ψd(intra) and/or Ψd(extra), thereby increasing or decreasing the energy barriers governing channel gating transitions. We used quantum mechanical and molecular dynamics (MD) simulations to predict the overall Ψd-modulating effects of a series of published positive hERG potentiators partitioned into model DOPC bilayers. Our findings suggest a strong correlation between the magnitude of Ψd-lowering and positive hERG potentiation across the series.