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Symbol KCNH2 contributors: mct - updated : 21-09-2018
HGNC name potassium voltage-gated channel, subfamily H (eag-related), member 2
HGNC id 6251
Corresponding disease
BRGS10 Brugada syndrome 10
LQT2 long QT syndrome with ventricular tachyarrhythmia, type 2
SQT1 short QT syndrome-1
Location 7q36.1      Physical location : 150.642.049 - 150.675.014
Synonym name
  • human ether-a-go-go related gene
  • ether-a-go-go-related gene potassium channel 1
  • cause of Long QT Syndrome Type 2
  • potassium channel HERG1
  • Eag-related protein 1
  • Synonym symbol(s) HERG, LQT2, ERG1, SQT1, HERG1, Kv11.1
    TYPE functioning gene
    STRUCTURE 33.36 kb     15 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D7S2450 - KCNH2 - D7S483 - SLC4A2 - D7S550 - qter
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - - 3575 - 1058 smooth muscle specific 2002 12427763
  • also called ERG1 sm
  • truncated C terminus of 101 amino acids, stop codon of the exon 14
  • 11 - 3191 - 819 in the heart, colon 2002 12427763
    alsos called HERG1B or variant 3/isoform c
    9 - 3164 - 888 in the heart 2002 12427763
  • also called HERG uso or variant 2/isoform b
  • 15 exons, alternatively spliced variant at exon 9 of HERG1 , truncated isoform
  • has an alternate 36-AA N-terminal end
  • 15 splicing 4307 126.7 1159 - 2002 12427763
    also called ERG1 Ia or variant 1/isoform a
    - - 4720 - - brain-specific 2002 12427763
  • also called KCNH2-3.1 FJ938021
  • lacks a domain that is crucial for slow channel deactivation
  • overexpression in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, nonadapting firing pattern
  • KCNH2-3.1 mRNA expression was significantly increased within the hippocampal formation of subjects with schizophrenia versus healthy control subjects
  • lacks the first 102AA of hERG1a, which are replaced by 6 unique amino acids
  • 5 - 2463 - 548 - 2002 12427763
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiens
    Digestiveintestinesmall intestine   
     intestinelarge intestinecolon highly
    Endocrineparathyroid   highly
    Nervousbrain     Homo sapiens
    Reproductivefemale systemovary  highly
    Urinarykidney   highly
    Visualeye   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularsmooth    Homo sapiens
    SystemCellPubmedSpeciesStageRna symbol
    Muscularmyocyte Homo sapiens
    cell lineage
    cell lines
    at STAGE
  • cytosolic N terminus domain, highly conserved, controlling desactivation by association with K+ channel, with a Per-Arnt-Sim (PAS) domain, regulating its deactivation kinetics , PAS domain that is also implicated in the assembly and stabilization of the assembled tetrameric channel
  • six membrane spanning domains with an hydrophobic pore flanked by TM domains 5 and 6
  • arginine-rich fourth TM domain controling voltage dependent gating
  • one cyclic nucleotide binding domain
  • a voltage-sensor domain (VSD) that is important for sensing voltage changes across the membrane
  • cytosolic C terminus, with significant role in cardiac repolarization, sensitive to changes in membrane potential (PAS associated C terminal domain-Par)
  • C-terminal region containing a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore; it is required for the channel gating though molecular interactions with the eag domain
  • secondary structure
  • when the PAS domain is present, the N-Cap amphipathic helix must also be present for channels to traffic to the cell membrane
    interspecies homolog to Drosophila eag
    homolog to murine Dcnh2
    intraspecies homolog to cyclic nucleotide gated channel
  • potassium channel family
  • H (Eag) subfamily
  • CATEGORY motor/contractile , transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
    intracellular,nuclear envelope
  • KCNH2 expression in the plasma membrane is regulated by CAV3 via NEDD4L
  • basic FUNCTION
  • potassium voltage-gated channel
  • similar to IKr, the cardiac rapid delayed rectified potassium channel
  • mediating the rapidly activating component of the delayed rectifying potassium current in heart (IKr)
  • forms the ion channel responsible for the rapidly acting delayed rectifier potassium current, I(Kr), and its blockade is a significant contributor to prolongation of the QT interval
  • alpha-subunit of the potassium channel underlying the rapid component of the cardiac delayed rectifier current
  • contribute to threshold excitability (potential link between auditory hyperexcitability and acoustic startle triggering of cardiac events in familial LQT2)
  • during biogenesis of channels KCNH2, is more likely to assemble with KCNE1 than KCNE2 due to distinctly different trafficking rates and retention in the cell rather than differences in relative affinity
  • plays an essential role in the final repolarization of the ventricular action potential
  • plays an important role in the repolarization of cardiac action potentials, and alterations therein can cause life-threatening cardiac arrhythmias
  • pore-forming subunit of the rapid component of the delayed rectifier K(+) channel
  • essential for cardiac repolarization but is also a source of cardiotoxicity because unintended KCNH2 inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death
  • inward rectifier voltage-gated potassium channel, of primary importance for the regulation of the membrane potential of cardiomyocytes
  • potassium channel that conducts the rapidly activating delayed rectifier current in the heart
  • is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current
  • encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization
    a component
  • part of ERG channels control the excitability of medial vestibular nucleus neurones, their discharge regularity and probably their resonance properties
  • CAV3, NEDD4L, and KCNH2 likely form a complex in the plasma membrane
    small molecule
  • PRKACA-dependent regulation of KCNH2 synthesis occurs at the ER surface
  • function of APC/CTNNB1 in the regulation of KCNH2 channels
  • direct interactions between KCNQ1 and KCNH2 occuring in both intact heterologous cells and primary cardiomyocytes and are mediated by their COOH termini
  • CAV3 enhances ubiquitin ligase NEDD4L interaction with mature KCNH2 channels in the plasma membrane, leading to decreased channel expression
  • SGK1 enhances the expression level of mature KCNH2 channels by inhibiting NEDD4L as well as by promoting RAB11-mediated KCNH2 recycling (PMMID: 23589291)
  • RAB4A decreases the KCNH2 density at the plasma membrane by increasing the endogenous NEDD4L expression
  • RNF207 is an important regulator of action potential duration, likely via effects on KCNH2 trafficking and localization in a heat shock protein-dependent manner
  • GTPase RAB11A, is involved in the recycling of KCNH2
  • NDFIP1 is primarily localized in the Golgi apparatus where it recruits NEDD4L to mediate the degradation of mature KCNH2 proteins during channel trafficking to the plasma membrane
  • damage of KCNH2 mediated by proteases such as calpain may contribute to ischemia-associated QT prolongation and sudden cardiac death
  • TBX20 can be considered a KCNH2-modifying gene
  • hypoxia reduces mature KCNH2 channels through calpain up-regulation
  • cell & other
    inhibited by acidic pH inhibiting KCNH2 channel maximal conductance and accelerating deactivation, likely by different mechanisms
    Other undergo ER export in COPII vesicles and endosomal recycling prior to being processed in the Golgi
    regulated by FHL2 (interacts with and regulates the KCNH2 channel)
    corresponding disease(s) LQT2 , SQT1 , BRGS10
    related resource Long QTSyndrome Database
    Long QT Syndrome Database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    marks an early step of the progression of normality to cancer in the esophagus through a metaplastic and dysplastic stage
    tumoral       gain of function
    in endometrial cancers (absent in endometrial hyperplasia)
    tumoral     --over  
    in myelodysplastic syndromes (MDS)
    constitutional       loss of function
    results in defects in cardiogenesis and vasculogenesis
  • to arhytmic events when mutation in the pore region (in LQT2 patients)
  • to schizophrenia
  • to sudden infant death syndrome (with short or long QT)
  • Variant & Polymorphism SNP , other
  • 2690A>C increasing the risk of arrhythmia or sudden death
  • Six SNPs were significantly associated with schizophrenia
  • variants associated to sudden infant death syndrome (with short or long QT)
  • Candidate gene
  • might be a potential tumor marker of MDS
  • Therapy target
    inhibition of KCNH2 might be a novel therapeutic measure for MDS (myelodysplastic syndrome)