Molecular Determinants in K+ Channel hERG Inactivation Gating

Abstract

Voltage-gated K+ (Kv) channels play a crucial role in the generation of cellular action potentials. Kv channels open and close in response to changes in transmembrane voltage. A further regulatory mechanism is channel inactivation, which occurs at the K+ selectivity filter and is of particular importance in the cardiac K+ channel hERG, that plays a major role in controlling the human heart rate. In a series of molecular dynamics simulations, we identified an extensive hydrogen bond network around residues S620 and N629 that controls the conformation of the selectivity filter and should therefore have a great impact on inactivation. We show that the distance of N629 to S620 acts as a nearly linear switch to drive the K+ selectivity filter from its conductive to a collapsed state similar to the low K+ conformation of KcsA. Electrophysiological measurements on mutants with altered H-bonding networks display either reduced or even fully abolished inactivation and thus support our hypothesis. Additionally, our simulations revealed a sidepocket extending from the central cavity, only present in the conductive state. These pockets are sufficently large to accommodate molecules of the newly found class of hERG-activators and reveal a first hint at their putative molecular mechanism.