Interaction between the Cardiac Rapidly (IKr) and Slowly (IKs) Activating Delayed Rectifier Potassium Channels Revealed by Low K+-induced hERG Endocytic Degradation

Cardiac repolarization is controlled by the rapidly (IKr) and slowly (IKs) activating delayed rectifier potassium channels. The human ether-a-go-go-related gene (hERG) encodes IKr, whereas KCNQ1 and KCNE1 together encode IKs. Decreases in IKr or IKs cause long QT syndrome (LQTS), a cardiac disorder...

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Published in:	The Journal of biological chemistry 2011-10, Vol.286 (40), p.34664-34674
Main Authors:	Guo, Jun, Wang, Tingzhong, Yang, Tonghua, Xu, Jianmin, Li, Wentao, Fridman, Michael D., Fisher, John T., Zhang, Shetuan
Format:	Article
Language:	eng
Subjects:	Animals Biophysics Biophysics - methods Cardiac Muscle Cell Biology Cell Membrane - metabolism Delayed Rectifier Potassium Channels - metabolism Electrophysiology - methods Endocytosis ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels - physiology Gene Expression Heart - physiology Humans Hypokalemia - metabolism Ion Channels KCNQ1 Potassium Channel - metabolism Kidney - embryology Myocardium - metabolism Potassium - metabolism Potassium Channels Potassium Channels, Voltage-Gated - metabolism Rabbits Trafficking
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Summary:	Cardiac repolarization is controlled by the rapidly (IKr) and slowly (IKs) activating delayed rectifier potassium channels. The human ether-a-go-go-related gene (hERG) encodes IKr, whereas KCNQ1 and KCNE1 together encode IKs. Decreases in IKr or IKs cause long QT syndrome (LQTS), a cardiac disorder with a high risk of sudden death. A reduction in extracellular K+ concentration ([K+]o) induces LQTS and selectively causes endocytic degradation of mature hERG channels from the plasma membrane. In the present study, we investigated whether IKs compensates for the reduced IKr under low K+ conditions. Our data show that when hERG and KCNQ1 were expressed separately in human embryonic kidney (HEK) cells, exposure to 0 mm K+ for 6 h completely eliminated the mature hERG channel expression but had no effect on KCNQ1. When hERG and KCNQ1 were co-expressed, KCNQ1 significantly delayed 0 mm K+-induced hERG reduction. Also, hERG degradation led to a significant reduction in KCNQ1 in 0 mm K+ conditions. An interaction between hERG and KCNQ1 was identified in hERG+KCNQ1-expressing HEK cells. Furthermore, KCNQ1 preferentially co-immunoprecipitated with mature hERG channels that are localized in the plasma membrane. Biophysical and pharmacological analyses indicate that although hERG and KCNQ1 closely interact with each other, they form distinct hERG and KCNQ1 channels. These data extend our understanding of delayed rectifier potassium channel trafficking and regulation, as well as the pathology of LQTS. Background: A reduction in either IKr or IKs can cause long QT syndrome. Results: Enhanced endocytic degradation of IKr decreases the expression of both IKr and IKs in the plasma membrane. Conclusion: IKr and IKs form a macrocomplex at the plasma membrane. Significance: Elucidation of IKr-IKs interaction is important for understanding the pathology of cardiac arrhythmias and designing anti-arrhythmic strategies.
ISSN:	0021-9258 1083-351X