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.

Keywords: gating; heterogeneity; phosphorylation; trafficking.

Figure 1. KCNE1 β‐subunits alter the gating of Kv7.1 channels

A, Kv7.1 channels are formed by co‐assembly of four identical α‐subunits, each composed of six transmembrane segments. Co‐assembly of Kv7.1 channels with KCNE1 β‐subunits (single transmembrane domain) form slowly activating channels that conduct cardiac I _Ks in cardiac myocytes. B, KCNE1 subunits alter the voltage dependence of voltage sensor movement. The F–V relationship is shifted to more negative potentials, whereas the G–V relationship is shifted to more positive potentials. C, simplified kinetic model of Kv7.1 and I_Ks channel gating. Fourth power notation symbolizes four VSDs per channel. KCNE1 subunits suppresses channel opening when the VSDs are in the intermediate‐open (IO) state and stabilizes the activated‐open (AO) state. Modified from Zaydman et al. (2014).

Figure 2. Cardiac K⁺ channel diversity

A, AP regional heterogeneity; redrawn from Bartos et al. (2015). B, K⁺ currents during ventricular and atrial APs; redrawn from Schmitt et al. (2014). C, species differences in ventricular AP; redrawn from Kaese & Verheule (2012).

Figure 3. Mechanisms for regulation of cardiac K⁺ channels

A, transcriptional regulation; B, interacting proteins; C, post‐translational modifications; D, ligands, Ca²⁺ and calmodulin; E, membrane lipids; F, co‐assembly of subunits; G, forward trafficking, including packaging into COPII‐coated vescicles, transport to ER‐Golgi intermediate compartament and Golgi apparatus, and trafficking to specific membrane destinations into clathrin‐coated vescicles; H, internalization.