Deciphering hERG channels: molecular basis of the rapid component of the delayed rectifier potassium current.

The rapid component of the delayed rectifier potassium current (I(Kr)), encoded by the ether-a-go-go-related gene (ERG1, officially denominated as KCNH2), is a major contributor to repolarization in the mammalian heart. Acute (e.g. drug-induced) and chronic (e.g. inherited genetic disorder) disruptions of this current can lead to prolongation of the action potential and potentiate occurrence of lethal arrhythmias. Many cardiac and non-cardiac drugs show high affinity for the I(Kr) channel and it is therefore extensively studied during safety pharmacology. The unique biophysical and pharmacological properties of the I(Kr) channel are largely recapitulated by expressing the human variant (hERG1a) in overexpressing systems. hERG1a channels are tetramers consisting of four 1159 amino acid long proteins and have electrophysiological properties similar, but not identical, to native I(Kr). In the search for an explanation to the discrepancies between I(Kr) and hERG1a channels, two alternative hERG1 proteins have been found. Alternative transcription of hERG1 leads to a protein with a 56 amino acid shorter N-terminus, known as hERG1b. hERG1b can form channels alone or coassemble with hERG1a. Alternative splicing leads to an alternate C-terminus and a protein known as hERGuso. hERGuso and hERG1b regulate hERG1a channel trafficking, functional expression and channel kinetics. Expression of hERGuso leads to a reduced number of channels at the plasma membrane and thereby reduces current density. On the contrary, co-assembly with hERG1b alters channel kinetics resulting in more available channels and a larger current. These findings have implication for understanding mechanisms of disease, acute and chronic drug effects, and potential gender differences.