J Physiol 595.7 (2017) pp 2209–2228 2209
WHITE PAPER Potassium channels in the heart: structure, function and regulation
Eleonora Grandi1, Michael C. Sanguinetti2, Daniel C. Bartos1,DonaldM.Bers1, Ye Chen-Izu1,3, Nipavan Chiamvimonvat3, Henry M. Colecraft4, Brian P. Delisle5, Jordi Heijman6 , Manuel F. Navedo1, Sergei Noskov7, Catherine Proenza8, Jamie I. Vandenberg9 and Vladimir Yarov-Yarovoy10
1Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA 2Department of Internal Medicine, University of Utah, Nora Eccles Harrison Cardiovascular Research and Training Institute, Salt Lake City, UT 84112, USA 3Department of Internal Medicine, Division of Cardiology, University of California, Davis, CA 95616, USA 4Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA 5Department of Physiology, University of Kentucky, Lexington, KY 40536, USA 6Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands 7Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 1N4, Canada 8Department of Physiology and Biophysics, University of Colorado - Anschutz Medical Campus, Denver, CO 80045, USA 9Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia 10Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA
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,
The Journal of Physiology 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.
(Received 28 May 2016; accepted after revision 18 July 2016) Corresponding author E. Grandi: Department of Pharmacology, Genome and Biomedical Sciences Facility, Room 3502, University of California, Davis, Davis, CA, USA. Email: [email protected]
Abbreviations AF, atrial fibrillation; AP, action potential; APD, action potential duration; CaMKII, Ca2+/calmodulin-dependent protein kinase II; COP, coatamer associated protein; cryo-EM, cryo-electron microscopy; ER, endoplasmic reticulum; HF, heart failure; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; + IPC, ischaemic preconditioning; KV,voltage-gatedK ; LQTS, long QT syndrome; MD, molecular dynamics; PIP2, phosphatidylinositol-4,5-bisphosphate; REFER, rate-equilibrium free energy; RMP, resting membrane potential; SR, sarcoplasmic reticulum; SUR, sulfonylurea receptor; VSD, voltage sensor domain.