Background:The hERG-encoded potassium channel I Kr is important for cardiac repolarization. Results: Internalized hERG channels are recycled back to the plasma membrane through a Rab11-associated pathway. Conclusion: Recycling plays an important role in the homeostasis of hERG channels. Significance: Identification of hERG recycling is useful for understanding hERG dysfunction and for developing new strategies to rescue hERG function.

The human ether‐a‐go‐go‐related gene (hERG) encodes the α‐subunit of the rapidly activating delayed rectifier potassium channel (IKr). A reduction in hERG expression on the plasma membrane causes long QT syndrome, predisposing affected individuals to high risk of cardiac arrhythmias and sudden death. We previously reported that plasmalemmal hERG channels are vigorously internalized under certain conditions such as hypokalemia. Whether internalized channels can recycle back to the membrane remains unknown. In this study, using Western blot and patch clamp techniques, we observed that an enhanced recovery rate of IKr is associated with an increased endocytosis of hERG channels after exposure of cells to hypokalemic conditions. This observation is not due to increased synthesis since hERG mRNA expression was not increased by hypokalemic treatment and the enhanced recovery was not affected by the inhibition of protein synthesis using cycloheximide. Using fluorescent labeling, we directly monitored the retrieval trafficking of internalized hERG channels to the plasma membrane. Co‐immunoprecipitation experiments reveal that hERG channels are associated with the GTPase Rab11, but not Rab4. Interference with Rab11 function but not Rab4 led to decreased hERG expression and function. Our data provide novel insights into the recycling mechanisms that regulate the homeostasis of membrane‐bound hERG channels. Supported by the Canadian Institutes of Health Research ‐ CIHR