Human ether-à-go-go–related gene potassium channel (hERG (also known as Kv11.1))

The human ether-à-go-go–related gene potassium channel (hERG, encoded by KCNH2) forms the alpha subunit of a voltage-gated delayed rectifier potassium ion channel known as Kv11.1. This ion channel is essential for mediating the rapid component of the delayed rectifier K+ current (IKr) that contributes critically to repolarization during phase three of the cardiac action potential. Dysfunction—whether due to genetic mutation or drug-induced blockade—can result in dangerous prolongation of ventricular repolarization seen clinically as long QT syndrome type 2; this predisposes individuals to potentially fatal ventricular tachyarrhythmias like torsades de pointes. The protein consists of four identical subunits forming a central pore with six transmembrane segments per subunit; it features unique gating kinetics characterized by rapid voltage-dependent inactivation coupled with slow deactivation—a property regulated via interactions between its N-terminal PAS domain and C-terminal cyclic nucleotide binding homology domain. The structure has been elucidated using cryo-electron microscopy techniques, which has advanced understanding for rational drug design targeting this molecule. Beyond its role in cardiomyocytes, hERG channels are also expressed at lower levels in neurons and some tumor cells where they may influence cell proliferation or differentiation pathways, making them relevant both as therapeutic targets—and antitargets—in oncology research. Because so many unrelated pharmaceuticals can inadvertently block hERG channels leading to adverse cardiac events, screening against this target is now standard practice during preclinical drug development.

Other names

hERG potassium channelKv11.1KCNH2 (gene name)IKr channel (refers to the current mediated by this channel)Ether-à-go-go–related gene potassium channel

For blockers/inhibitors: Blockade of the hERG/Kv11.1 pore reduces IKr current, prolonging cardiac action potential duration and QT interval on ECG; this can lead to arrhythmia or torsades de pointes if excessive. For activators/modulators: Some agents may enhance or alter gating kinetics but these are less common clinically.