Extracellular K+ is a prerequisite for the function and plasma membrane stability of HERG channels.

Rationale: The human ether-a-go-go-related gene (HERG) encodes the pore-forming subunits of the rapidly activating delayed rectifier potassium channel (I(Kr)) that is important for cardiac repolarization. Dysfunction of HERG causes long QT syndrome (LQTS) which can lead to sudden cardiac death. We previously showed that a reduction in extracellular K(+) concentration ([K(+)](o)) prolongs QT intervals in intact rabbits, and decreases the cell surface density of I(Kr) in rabbit ventricular myocytes and of the HERG channel expressed in human embryonic kidney (HEK) cells.

Objective: The goal of the present study was to gain insights into the mechanisms for low [K(+)](o) induced reduction in HERG expression levels.

Methods And Results: Using patch clamp, Western blot and confocal imaging methods, we demonstrated that at low [K(+)](o), the HERG channel entered a novel nonconducting state. Furthermore, this novel functional state triggered rapid internalization and degradation of the cell surface HERG channels. Thus, our data demonstrated for the first time a direct link between a gating state and the plasma membrane stability of an ion channel, HERG. Using HERG-permeant cations and site-directed mutagenesis, we identified the sites in the channel which are involved in the K(+)(o) dependence of HERG channels.

Conclusions: Extracellular K(+) is a prerequisite for HERG function and membrane stability.