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FLASH GENE
Symbol KCNH2 contributors: mct - updated : 14-10-2013
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
    DNA
    TYPE functioning gene
    STRUCTURE 32.97 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
    Physical map
    LOC389599 7 similar to amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 2; ILP-interacting protein ILPIPA hIAN7 7q36.1 immune associated nucleotide ATQL3 7q36 antiquitin-like 3 HIMAP4 7q36.1 immunity associated protein 4 LOC392149 7 similar to transient receptor potential cation channel, subfamily C, member 6; transient receptor potential channel 6 hIAN2 7q36.1 human immune associated nucleotide 2 HIMAP2 7q36.1 immunity associated protein 2 IMAP1 7q36.1 immunity associated protein 1 IAN4L1 7q32-q36 immune associated nucleotide 4 like 1 (mouse) LOC392150 7 similar to immune associated nucleotide 4 like 1; immunity associated protein 3 LOC392151 7 similar to BET1 homolog (Golgi vesicular membrane trafficking protein p18) (hBET1) LR8 7q36.1 LR8 protein HCA112 7q36.1 hepatocellular carcinoma-associated antigen 112 ABP1 7q34-q36 amiloride binding protein 1 (amine oxidase (copper-containing)) KCNH2 7q35-q36 potassium voltage-gated channel, subfamily H (eag-related), member 2 NOS3 7q36 nitric oxide synthase 3 (endothelial cell) FLJ39415 7q36.1 hypothetical protein FLJ39415 ABCB8 7q35-q36 ATP-binding cassette, sub-family B (MDR/TAP), member 8 ACCN3 7q35 amiloride-sensitive cation channel 3, testis CDK5 7q36 cyclin-dependent kinase 5 SLC4A2 7q35-q36 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1) FASTK 7q35 FAST kinase C7orf21 7q36.1 chromosome 7 open reading frame 21 CENTG3 7q36.17q36.1 centaurin, gamma 3 LOC392152 7 similar to gastrulation brain homeobox 1 ASB10 7q35 ankyrin repeat and SOCS box-containing 10 LOC155046 7q36.1 similar to hypothetical protein 4931409K22 LOC346545 7q36.1 similar to hypothetical protein FLJ22527 ABCF2 7q35-q36 ATP-binding cassette, sub-family F (GCN20), member 2 CSGlcA-T 7q36.1 KIAA1402 protein SMARCD3 7q35-q36 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 3 NYREN18 7q36 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 3
    RNA
    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 2010 20693282
    alsos called HERG1B or variant 3/isoform c
    9 - 3164 - 888 in the heart 2010 20693282
  • 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 - 2010 20693282
    also called ERG1 Ia or variant 1/isoform a
    - - 4720 - - brain-specific 2010 20693282
  • 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
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    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
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularsmooth    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    Muscularmyocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • cytosolic N terminus domain, highly conserved, controlling desactivation by association with K+ channel, with a Per-Arnt-Sim (PAS) domain, regulating its deactivation kinetics
  • 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
  • one PAS dimerization 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
  • HOMOLOGY
    interspecies homolog to Drosophila eag
    homolog to murine Dcnh2
    intraspecies homolog to cyclic nucleotide gated channel
    Homologene
    FAMILY
  • potassium channel family
  • H (Eag) subfamily
  • CATEGORY motor/contractile , transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm
    intracellular,nuclear envelope
    text
  • 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
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    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
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • 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
  • cell & other
    REGULATION
    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)
    ASSOCIATED DISORDERS
    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)
    Susceptibility
  • 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
    Marker
    Therapy target
    ANIMAL & CELL MODELS