Caution: merging ion channel traffic ahead

Abstract

KCNH2, also known as the human ether-à-go-go related-gene or hERG, encodes the Kv11.1 channel proteins that conduct the rapidly activating delayed rectifier K+ current (IKr) in the heart. IKr plays a primary role in ventricular repolarization, and a decrease or loss in IKr is associated with an increased risk for the deadly cardiac arrhythmias (Sanguinetti et al., 1995). A major goal in cardiac safety assessment is to identify mechanisms that modify IKr, ventricular repolarization, and arrhythmogenic risk. To understand how IKr can be modified, one can think of IKr as being equal to the number of Kv11.1 channels in the membrane (M), the open probability of the Kv11.1 channels (Po), and the amplitude of the single Kv11.1 channel current (i) (Hille, 2001): IKr = MPoi. Po and i reflect the biophysical properties of Kv11.1 channels in the cell membrane. In contrast, M reflects several different cytoplasmic processes, including Kv11.1 channel trafficking, production and degradation. The kinetics of the cytoplasmic processes that regulateM are orders of magnitude slower than the biophysical properties that regulate Po and i (Fig. 1). As a result, modifying Po and i has an immediate impact on IKr and ventricular repolarization, whereas modifying the cytoplasmic processes that regulate M take minutes, hours or even days to fully impact IKr, ventricular repolarization and arrhythmia susceptibility. In this issue of The Journal of Physiology, Meier and colleagues recognized this and developed a model to calculate how changes in the cytoplasmic processes that regulate the number of Kv11.1 channels in the membrane (M), IKr and ventricular repolarization (Meier et al., 2023). To do this, they integrate their model with the O’Hara–Rudy (ORd) ventricular action potential (AP) model (O’Hara et al., 2011). They apply the integrated model to predict how conditions that alter the biophysical properties and number of Kv11.1 channels in the membrane impact IKr and the ventricular AP waveform. This Perspective article provides a primer for how Meier and colleagues modelled the cytoplasmic processes that regulate channel number, and it highlights their important contribution in understanding time-dependent changes in arrhythmogenic risk. Meier and colleagues introduce a two-state kinetic model for the trafficking of an ion channel to the membrane, where the variable M represents the number of channels in the membrane and S the number in the cytoplasm. The number of channels in the membrane increases with membrane insertion and decreases with