Febrile temperature decreases the cell‐surface expression of the human ether‐a‐go‐go‐related gene (hERG) channel by facilitating channel degradation (949.3)

The human‐ether‐a‐go‐go‐related gene (hERG) encoded I Kr and KvLQT1+minK encoded I Ks are primary K + currents responsible for cardiac repolarization in many species including humans. Dysfunction of either I Kr or I Ks can lead to long QT syndrome (LQTS), which predisposes the affected individuals to arrhythmias, syncope, or sudden death. Recent studies have reported that fever may serve as a trigger for QT interval prolongation and arrhythmias in patients. In the present study, we investigated the effect of febrile temperature on hERG and KvLQT1+minK channels using Western blot, patch clamp, and immunocytochemistry. Our data show that culturing cells in febrile temperature (40°C) reduced the expression and current amplitude of hERG channels stably expressed in HEK cells as well as I Kr in neonatal rat cardiomyocytes. However, this manipulation did not reduce KvLQT1+minK current. Our data further show that accelerated protein degradation is responsible for the reduced plasma abundance of hERG channels. We have previously shown that hypokalemia accelerates hERG degradation and reduces hERG expression at the plasma membrane. Our data revealed that a reduction in K + greatly exaggerated, and K + insensitive mutation S624T completely abolished febrile temperature ‐induced hERG degradation. We conclude that febrile temperature may facilitate the development of LQTS via accelerating hERG degradation. Supported by the Canadian Institutes of Health Research (CIHR). Grant Funding Source : Supported by Canadian Institutes of Health Research