Extracellular K+ Is a Prerequisite for the Function and Stability of HERG Channels in the Plasma Membrane

Abstract

The human Ether-a-go-go related gene (HERG) encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of HERG causes long QT syndrome (LQTS), which can lead to sudden cardiac death. Using an in vivo rabbit model, we demonstrated that a reduction in extracellular K+ concentration ([K+]o), known as hypokalemia, causes LQTS and sudden death. Our data demonstrated that hypokalemia chronically reduces IKr and prolongs the action potential duration in rabbit ventricular myocytes. Using cell expression systems, we found that extracellular K+ (K+o) is a prerequisite for HERG function and membrane stability; upon depletion of K+o, HERG channels enter into a non-conducting state within minutes and are subsequently internalized and degraded within hours. The conductance loss in low K+ reflects a conformational change of the HERG channel, which causes the channel to be tagged by ubiquitin. Attachment of ubiquitin triggers HERG channel internalization through a caveolin-dependent endocytic pathway. Internalized HERG channels are co-localized with multivesicular bodies and are targeted to lysosomes for degradation. Our results provide the first evidence that the cell surface density of a voltage-gated K+ channel, HERG, is regulated by a biological factor, extracellular K+. Since hypokalemia is known to exacerbate LQTS and Torsade de Pointes tachyarrhythmias in humans, our findings provide a novel mechanistic link between hypokalemia and LQTS.