Potassium channels in the heart: structure, function and regulation

Abstract

This paper is the outcome of the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium, a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2016 symposium was 'K Channels and Regulation'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies and challenges on the topic of cardiac K channels. This paper summarizes the topics of formal presentations and informal discussions from the symposium on the structural basis of voltage-gated K channel function, as well as the mechanisms involved in regulation of K channel gating, expression and membrane localization. Given the critical role for K channels in determining the rate of cardiac repolarization, it is hardly surprising that essentially every aspect of K channel function is exquisitely regulated in cardiac myocytes. This regulation is complex and highly interrelated to other aspects of myocardial function. K channel regulatory mechanisms alter, and are altered by, physiological challenges, pathophysiological conditions, and pharmacological agents. An accompanying paper focuses on the integrative role of K channels in cardiac electrophysiology, i.e. how K currents shape the cardiac action potential, and how their dysfunction can lead to arrhythmias, and discusses K channel-based therapeutics. A fundamental understanding of K channel regulatory mechanisms and disease processes is fundamental to reveal new targets for human therapy.

Aloe-Emodin Relieves High-Fat Diet Induced QT Prolongation via MiR-1 Inhibition and IK1 Up-Regulation in Rats

“…The electrical activity of the heart is an extraordinary arrangement by multiple categories of ion channels, and the movement of ions across the cytoplasmic membrane of cardiomyocytes is controlled by transmembrane proteins [32]. The membrane potential and the rate of membrane repolarization are managed by potassium (K + ) channels [33]. Among these channels, I K1 is a strong inward rectifier K + -selective current, which plays important roles in modulating the RMP and the final repolarization phase of action potential in cardiomyocytes [34].…”

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

“…It has been shown that drugs with similar binding affinity but different binding kinetics can have diverse effects[3, 149, 150]. The most commonly used metric for drug blockade is IC 50 , but it provides an average measure of drug potency to supress ion currents without any mechanistic insights.…”

“…Unsurprisingly, ion channels have been among the most common drug targets for decades of treatment efforts and novel drug development. While many ion channel targets are known (for example pace-maker channels: HCNs), the development of drugs that act as highly ion channel specific modulators remains challenging[3]. High-throughput technologies, animal models, detailed biochemical and biophysical explorations are all dispatched to identify potential leads with high specificity to a transmembrane protein.…”

“…The ability to move ions selectively from one side of the membrane to another rapidly changing local ionic concentrations and hence electrochemical potentials on the surface is central for the generation of specific cellular response known as Action Potentials (AP). The APs are membrane-depolarizing waves, whose patterns and durations are critical for normal physiology [3]. Therefore, various mutations or drug binding that impact selective permeation or gating process may potentially be harmful.…”

“…However, only a small set of experimental (either closed or open, or very few intermediate) structures is available for an ion channel, thus hindering the study of the state-dependence binding of drugs. Ion Channels do exist in multiple states with rapid (μs-ms) conformational changes triggered by membrane voltage changes and other ligand stimuli[3]. But the interconnections among all metastable states, on which specific drug bindings and cellular responses can be connected, are missing.…”