An Insight into the Potassium Currents of hERG and Their Simulation

Abstract

By assuming that a stepwise outward movement of the four S4 segments of the hERG potassium channel determines a concomitant progressive increase in the flow of the permeant potassium ions, the inward and outward potassium currents can be simulated by using only one or two adjustable (i.e., free) parameters. This deterministic kinetic model differs from the stochastic models of hERG available in the literature, which usually require more than 10 free parameters. The K+ outward current of hERG contributes to the repolarization of the cardiac action potential. On the other hand, the K+ inward current increases with a positive shift in the transmembrane potential, in apparent contrast to both the electric and osmotic forces, which would concur in moving K+ ions outwards. This peculiar behavior can be explained by the appreciable constriction of the central pore midway along its length, with a radius < 1 Å and hydrophobic sacks surrounding it, as reported in an open conformation of the hERG potassium channel. This narrowing raises a barrier to the outward movement of K+ ions, inducing them to move increasingly inwards under a gradually more positive transmembrane potential.