Cardiac ion channels and signaling proteins – QT prolongation related

This entry refers to a collective group of proteins, primarily voltage-gated ion channels, that regulate the cardiac action potential and whose modulation is associated with the prolongation of the QT interval on an electrocardiogram (Roden, 2004, N Engl J Med). The most significant member is the Potassium voltage-gated channel subfamily H member 2 (KCNH2), commonly known as hERG, which conducts the rapid delayed rectifier current (IKr) (Sanguinetti & Tristani-Firouzi, 2006, Nature). Other key proteins in this category include the KCNQ1/KCNE1 complex (IKs), the SCN5A sodium channel, and the CACNA1C L-type calcium channel (Gintant et al., 2016, Expert Opin Drug Metab Toxicol). Drug-induced inhibition of these channels, particularly hERG, can lead to delayed repolarization, increasing the risk of life-threatening arrhythmias such as Torsades de Pointes (StatPearls, 2023). Consequently, these proteins are critical safety targets in drug development, requiring extensive screening to mitigate cardiotoxic risks (FDA/ICH E14 Guidance). Beyond hERG, modern safety pharmacology emphasizes the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative, which evaluates drug effects across multiple channels in this group to better predict clinical risk (Cavero & Holzgrefe, 2014, Expert Opin Drug Saf).

Other names

hERG and related cardiac channelsPro-arrhythmic cardiac ion channelsQT-related ion channelsCardiac safety ion channel panel

Inhibition of the rapid delayed rectifier potassium current (IKr), blockade of voltage-gated sodium channels (INa), or modulation of L-type calcium channels (ICa,L) (Roden, 2004; Gintant et al., 2016).