KCNH2 (potassium voltage-gated channel subfamily H member 2; HGNC:6251, NCBI Gene ID 3757) is a human locus mapped to chromosome band 7q36.1 that encodes voltage-gated potassium channel subunit Kv11.1 / hERG (1,159 aa). KCNH2 acts in cardiac action potential phase 3 repolarization (IKr current), together with hERG Potassium Channel Pharmacology, SCN5A (Nav1.5 Cardiac Channel Gene), and RYR2 (Cardiac Ryanodine Receptor Gene). Encodes the hERG (Kv11.1) potassium channel mediating the rapid delayed rectifier current IKr in cardiac repolarization.
Congenital Long QT syndrome type 2 (LQT2) & drug-induced torsades de pointes
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 15-exon gene on chromosome 7q36.1 encoding the 1,159-amino-acid human Ether-a-go-go-Related Gene (hERG) alpha subunit containing a cytoplasmic N-terminal PAS (Per-Arnt-Sim) domain, six transmembrane helices (S1–S6) with a K+-selective GFG signature sequence, and a C-terminal cyclic nucleotide-binding homology domain.
Cellular & Tissue Expression Profile: Expressed strongly in ventricular and atrial cardiac myocytes as hetero-tetrameric complexes of full-length hERG1a and N-terminally truncated hERG1b isoforms, with secondary expression in neural and smooth muscle tissues.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Conducts the rapid component of the delayed rectifier potassium current (IKr): channels open slowly during depolarization but rapidly inactivate, then recover swiftly from inactivation as the membrane begins to repolarize in phase 3, generating a resurgent outward K+ current that terminates the cardiac plateau and prevents early afterdepolarizations.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Heterozygous loss-of-function mutations (most commonly missense variants that impair endoplasmic reticulum folding and Golgi trafficking of Kv11.1 tetramers) cause congenital Long QT syndrome type 2 (LQT2) with auditory- or emotional-startle-triggered ventricular arrhythmias, whereas rare gain-of-function variants cause Short QT syndrome type 1 (SQT1).
Therapeutic & Clinical Pharmacology: Because the wide inner pore vestibule lined by aromatic residues Tyr652 and Phe656 promiscuously traps diverse small molecules, mandatory preclinical hERG patch-clamp screening and human iPSC-derived cardiomyocyte profiling are cornerstones of global CiPA safety pharmacology to prevent drug-induced QT prolongation and torsades de pointes.