Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines
Open Access
- 1 September 2009
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 119 (9), 2745-2757
- https://doi.org/10.1172/jci39027
Abstract
Although the modulation of ion channel gating by hormones and drugs has been extensively studied, much less is known about how cell surface ion channel expression levels are regulated. Here, we demonstrate that the cell surface density of both the heterologously expressed K+ channel encoded by the human ether-a-go-go–related gene (HERG) and its native counterpart, the rapidly activating delayed rectifier K+ channel (IKr), in rabbit hearts in vivo is precisely controlled by extracellular K+ concentration ([K+]o) within a physiologically relevant range. Reduction of [K+]o led to accelerated internalization and degradation of HERG channels within hours. Confocal analysis revealed colocalization between HERG and ubiquitin during the process of HERG internalization, and overexpression of ubiquitin facilitated HERG degradation under low [K+]o. The HERG channels colocalized with a marker of multivesicular bodies during internalization, and the internalized HERG channels were targeted to lysosomes. Our results provide the first evidence to our knowledge that the cell surface density of a voltage-gated K+ channel, HERG, is regulated by a biological factor, extracellular K+. Because hypokalemia is known to exacerbate long QT syndrome (LQTS) and Torsades de pointes tachyarrhythmias, our findings provide a potential mechanistic link between hypokalemia and LQTS.This publication has 40 references indexed in Scilit:
- Intracellular Potassium Stabilizes HumanEther-à-go-go-Related Gene Channels for Export from Endoplasmic ReticulumMolecular Pharmacology, 2009
- TrkA Receptor Endolysosomal Degradation is Both Ubiquitin and Proteasome DependentTraffic, 2008
- ESCRT complexes and the biogenesis of multivesicular bodiesCurrent Opinion in Cell Biology, 2008
- Persistent Atrial Fibrillation Is Associated With Reduced Risk of Torsades de Pointes in Patients With Drug-Induced Long QT SyndromeJournal of the American College of Cardiology, 2008
- Biogenesis and Function of Multivesicular BodiesAnnual Review of Cell and Developmental Biology, 2007
- The Molecular Mechanism of Hepcidin-mediated Ferroportin Down-RegulationMolecular Biology of the Cell, 2007
- A concentric circle model of multivesicular body cargo sortingEMBO Reports, 2007
- The channelopathies: novel insights into molecular and genetic mechanisms of human diseaseJCI Insight, 2005
- Mechanisms of Arsenic-Induced Prolongation of Cardiac RepolarizationMolecular Pharmacology, 2004
- Signals for Sorting of Transmembrane Proteins to Endosomes and LysosomesAnnual Review of Biochemistry, 2003