Febrile Temperature Facilitates Degradation of Human Ether-­a-­Go-­Go-­Related Gene (hERG) Channels

Abstract

The human ether-a-go-go-related gene (hERG) encodes the α subunit of the rapidly activating delayed rectifier K+ channel (IKr), which plays an essential role in human cardiac repolarization. Dysfunction of hERG caused by genetic mutations or drug-mediated effects can lead to long QT syndrome (LQTS), predisposing affected individuals to cardiac arrhythmias, syncope, and sudden death. Recently, studies have reported roles for fever in triggering QT prolongation and life-threatening cardiac arrhythmias in patients with congenital hERG mutations or in those with no familial or medical history related to LQTS. In contrast, cell culture at low temperature (27°C) can rescue mutation-related or drug-induced reduction in hERG expression and function in Human Embryonic Kidney (HEK) 293 cells stably expressing hERG channels. In this study, I investigated the hypothesis that hERG channel function is altered by increased temperature, the potential mechanisms responsible, and the role of such effect on fever-precipitated LQTS. Since hypokalemia (a low serum K+ concentration) accentuates hERG degradation and may occur concomitantly with fever, I also examined the effect of febrile temperature on hERG under low-K+ conditions. Using Western blot, electrophysiological, and immunocytochemical analyses, I found that culturing cells at febrile temperature (40°C) specifically reduced the expression and current amplitude of wild type (WT) hERG stably expressed in HEK293 cells. This reduction of cell-surface hERG is through accelerated degradation, mediated by extracellular K+: the K+ concentration to maintain half maximum of hERG conductance (EC50) was shifted from 0.5 mM at 37°C to 1.6 mM at 40°C after overnight cultures; and low K+-insensitive hERG mutations S624T and F627Y completely abolished both hypokalemia-and febrile temperature-induced reduction of IhERG. In neonatal rat ventricular myocytes, both febrile temperature and hypokalemia prolonged the cardiac action potential and selectively reduced IKr. Also, the in-vivo rabbit model showed that fever and hypokalemia induced in rabbits synergistically prolonged the QT interval on the electrocardiogram (ECG). These results indicate that febrile temperature may facilitate the development of LQTS through expediting hERG degradation, especially under conditions such as hypokalemia.