Interaction between the cardiac rapidly (I _Kr) and slowly (I _Ks) activating delayed rectifier potassium channels revealed by low K ⁺-induced herg endocytic degradation

Cardiac repolarization is controlled by the rapidly (I ^Kr) and slowly (I ^Ks) activating delayed rectifier potassium channels. The human ether-a-go-go-related gene (hERG) encodes I _Kr, whereas KCNQ1 and KCNE1 together encode I _Ks. Decreases in I _Kr or I _Kscause long QT syndrome (LQTS), a cardiac disorder with a high risk of sudden death.Areduction 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 I _Ks compensates for the reduced I _Kr 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,hERGdegradation led to a significant reduction in KCNQ1 in 0 mM K ⁺ conditions. An interaction between hERG andKCNQ1was identified in hERG+KCNQ1-expressing HEKcells. Furthermore,KCNQ1preferentially 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.