Potassium voltage-gated channel subfamily H member 2 (Kv11.1) (Kv11.1)

The Potassium voltage-gated channel subfamily H member 2 (Kv11.1), frequently referred to as hERG, is an essential alpha-subunit of the voltage-gated potassium channel responsible for the rapid delayed rectifier current (IKr) in cardiac myocytes [UniProt P51787]. This channel is vital for the terminal repolarization of the cardiac action potential, which ensures the proper timing of the heartbeat and prevents premature excitation [StatPearls, Long QT Syndrome]. Dysfunctional Kv11.1 channels, whether due to genetic mutations in the KCNH2 gene or unintended drug interactions, are the primary cause of Long QT syndrome (LQTS) [StatPearls, Long QT Syndrome]. Pharmacological blockade of this channel is a major safety concern in drug development because it can lead to Torsades de Pointes, a potentially fatal ventricular arrhythmia [FDA/ICH S7B Guidelines]. Due to its large, hydrophobic inner vestibule, the channel is susceptible to binding by a wide variety of chemical structures, making it a promiscuous target for off-target drug effects [PubChem KCNH2]. Consequently, regulatory agencies require rigorous hERG safety testing for almost all new drug candidates to mitigate the risk of cardiotoxicity [FDA/ICH S7B Guidelines]. Beyond its role in safety, Kv11.1 is also a therapeutic target for specific Class III antiarrhythmic drugs used to control heart rate and rhythm [PubChem KCNH2].

Other names

hERGhuman Ether-à-go-go-Related GenehERG1ERG1KCNH2

Drugs typically act as pore blockers, binding to the inner cavity of the channel and inhibiting the rapid delayed rectifier potassium current (IKr) [UniProt P51787, PubChem KCNH2].