Dickson, Callum, Pearlstein, Robert and Hornak, Viktor (2017) Contributions of the membrane dipole potential to the function of voltage-gated cation channels and modulation by small molecule potentiators. Biochimica et biophysica acta (BBA) - Biomembranes, 1859 (2). pp. 177-194. ISSN 00052736

Abstract

The dipole potential (Ψd) is a fundamental property of phospholipid bilayers, and the largest of three electric potentials existing within excitable membranes. Ψd arises in part from unfavorable alignment of phospholipid dipoles, and varies both temporally and spatially across bilayer surfaces, corresponding to the conformational states and locations of integral membrane proteins (increasing unfavorably in response to conformations promoting increased lipid packing density). Building on the work of Clarke, we propose that the transmembrane potential (ΔΨm) and Ψd serve as complementary barriers to voltage-gated cation channel activation and deactivation, respectively. Ψd serves as the energetic driving force for activation during depolarization, being opposed by ΔΨm in the resting state. Conversely, ΔΨm serves as the energetic driving force for deactivation during repolarization, being opposed by Ψd in the non-resting state. We further propose that modulation of Ψd by certain membrane-partitioned molecules alters the delicate balance between the two potentials, and thereby shifts the voltage dependence of voltage gated channel transitions. Here, we use molecular dynamics simulations to calculate Ψd modulation by a series of hERG activators partitioned in model POPC bilayers. Our findings suggest a strong correlation between Ψd lowering and hERG current increase across the series. Our hypothesis differs from the conventional view that potentiators act via direct ion channel binding, suggesting a plausible mechanism for 1) the transduction of binding energy into alteration of ion channel transition barriers (particularly under the non-equilibrium conditions found in vivo); and 2) both activator and inhibitor modalities, as may occur within the same chemical series.

Item Type:	Article
Date Deposited:	01 Dec 2016 00:45
Last Modified:	01 Dec 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28792