Structural changes associated with gating of voltage-gated potassium channels as suggested by pharmacological experiments

Abstract

Human Ether-à-go-go-Related Gene (hERG) encodes a potassium-selective voltage-gated ion channel essential for regular electrical activity in the heart but is also a major drug anti-target. Genetic hERG mutations and blockage of the channel pore by drugs can cause long QT syndrome (LQTS), which can lead to cardiac arrhythmia and even sudden cardiac death. In response to membrane depolarization, hERG channels undergo relatively slow activation and rapid inactivation. However, not all hERG-blocking drugs are pro-arrhythmic, and their differential affinities to discrete channel conformational states have been suggested to contribute to arrhythmogenicity. In my presentation, I will explain our recent pharmacological and docking studies and provide atomistic structural insights into state-dependent drug-channel interactions and the mechanism of gating modulations. I will discuss how some drugs have higher affinities to the inactivated state than others. I will also discuss why some hERG pore blockers facilitate channel activation to increase hERG currents. By considering the structural basis of these drug actions, I will finally propose the structural changes of the pore region, which is associated with the gating of voltage-gated potassium channels.