Affinage

KCNH2

Voltage-gated inwardly rectifying potassium channel KCNH2 · UniProt Q12809

Round 2 corrected
Length
1159 aa
Mass
126.7 kDa
Annotated
2026-04-28
130 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNH2 (hERG/Kv11.1) encodes the pore-forming α-subunit of the cardiac rapid delayed rectifier potassium current (IKr), a voltage-gated channel whose inward rectification arises not from intrinsic rectification but from rapid C-type-like inactivation that suppresses outward current at depolarized potentials (PMID:7604285, PMID:8587608). The channel's characteristically slow deactivation is governed by intracellular PAS-domain/cNBH-domain charge-charge interactions (Arg56–Asp803) and voltage-sensor relaxation stabilized by S3 acidic residues, while its cryo-EM structure reveals an unusually small central cavity flanked by deep hydrophobic pockets that explain its notorious susceptibility to drug block (PMID:28431243, PMID:25074935, PMID:30530765). Surface expression is tightly regulated by an Hsp70/Hsc70 chaperone balance that controls ubiquitination, FKBP38 co-chaperone-assisted trafficking, HDAC6-mediated deacetylation promoting degradation, and Rab11-dependent recycling, with the majority of LQT2 loss-of-function missense mutations acting through trafficking deficiency that is pharmacologically correctable (PMID:21183741, PMID:17569659, PMID:29355491, PMID:26152716, PMID:16432067). Loss-of-function mutations in KCNH2 cause long QT syndrome type 2 (LQT2) and gain-of-function mutations cause short QT syndrome type 1, both rescuable by a single suppression-and-replacement gene therapy construct in iPSC-cardiomyocytes (PMID:7889573, PMID:14676148, PMID:36252106).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Identification of HERG as the molecular basis of cardiac IKr and its linkage to LQT2 established the gene's central role in cardiac repolarization and arrhythmia susceptibility.

    Evidence Heterologous expression in Xenopus oocytes recapitulated IKr biophysics; linkage mapping and sequencing identified causative LQT2 mutations

    PMID:7604285 PMID:7736582 PMID:7889573

    Open questions at the time
    • Native heteromeric channel composition not yet defined
    • Mechanism of inward rectification not yet resolved at molecular level
  2. 1996 High

    The paradoxical inward rectification of HERG despite its depolarization-activated architecture was explained by rapid C-type-like inactivation, resolving a fundamental biophysical puzzle.

    Evidence Mammalian cell patch-clamp gating analysis distinguished inactivation from deactivation kinetics

    PMID:8587608

    Open questions at the time
    • Structural basis of C-type inactivation unknown
    • Relationship between inactivation gating and drug sensitivity not explored
  3. 1998 High

    Crystallography of the N-terminal PAS domain and identification of its role in slowing deactivation provided the first structural explanation for HERG's uniquely slow closing kinetics.

    Evidence X-ray crystallography combined with scanning mutagenesis and oocyte electrophysiology

    PMID:9845367

    Open questions at the time
    • PAS domain interaction partner on channel body not identified at residue level
    • Full-length channel structure unavailable
  4. 1999 High

    KCNE2 (MiRP1) was identified as an accessory β-subunit that reconstitutes native IKr properties, and HERG expression was demonstrated in neural tissue, broadening the channel's physiological context.

    Evidence Co-expression with single-channel recording and pharmacology in oocytes/mammalian cells; pharmacological dissection in neuroblastoma cells

    PMID:10219239 PMID:10479678

    Open questions at the time
    • Stoichiometry of KCNE2 in native IKr channels unresolved
    • Relative contribution of hERG to neuronal excitability in vivo unknown
  5. 2003 High

    Gain-of-function (N588K, short QT syndrome) and trafficking-defective loss-of-function mutations were characterized, revealing that HERG mutations cause disease through mechanistically distinct pathways including dominant-negative suppression and altered inactivation.

    Evidence Electrophysiology of multiple mutants in oocytes and mammalian cells; pharmacological correction of trafficking-deficient mutants; ERG1B knockout eliminating IKr

    PMID:12612061 PMID:12837749 PMID:14676148 PMID:9721698

    Open questions at the time
    • Comprehensive genotype-mechanism correlation across all LQT2 variants lacking
    • In vivo rescue of trafficking mutants not demonstrated
  6. 2006 High

    Systematic profiling of 34 LQT2 missense mutations established that ~80% act via trafficking deficiency correctable by pharmacological chaperones or low temperature, defining the predominant disease mechanism.

    Evidence Glycosylation shift assay, patch clamp, and pharmacological correction in HEK293 cells expressing 34 mutants

    PMID:16432067

    Open questions at the time
    • Patient-specific correction efficacy not tested
    • Long-term stability of rescued channels unknown
  7. 2006 High

    14-3-3ε binding to a PKA-phosphorylated C-terminal site was shown to amplify β-adrenergic regulation of HERG, and LQT2 C-terminal truncations were found to lose this regulatory input, explaining adrenergic-triggered arrhythmias.

    Evidence Co-expression in CHO cells with patch clamp, Western blot, and action potential simulation

    PMID:16923798

    Open questions at the time
    • In vivo relevance of 14-3-3ε interaction to arrhythmia triggers not confirmed
    • Phosphorylation site occupancy in native cardiomyocytes unquantified
  8. 2007 High

    A multi-layered chaperone/co-chaperone system controlling HERG surface expression was delineated: FKBP38 promotes trafficking, while Hsp70/Hsc70 balance determines ubiquitination and maturation efficiency.

    Evidence Proteomics screen, reciprocal co-IP, siRNA knockdown in HEK293 and HL-1 cardiomyocytes, heat shock experiments

    PMID:17569659 PMID:21183741

    Open questions at the time
    • Direct ubiquitin ligase identity for ER quality-control degradation incompletely defined
    • Chaperone interplay with pharmacological correction agents unexplored
  9. 2014 High

    Mutant cycle analysis identified the specific Arg56–Asp803 charge pair between PAS and cNBH domains as the energetic basis of slow deactivation, completing the intracellular gating model.

    Evidence Systematic mutagenesis with thermodynamic mutant cycle analysis and patch clamp in HEK293 cells

    PMID:25074935

    Open questions at the time
    • Structural visualization of PAS–cNBH interaction in full-length channel awaited cryo-EM confirmation
    • Contribution of N-Cap/C-linker interaction energetics less precisely quantified
  10. 2015 High

    Post-translational regulation of HERG surface density was further elaborated: Rab11-dependent recycling maintains steady-state expression, HDAC6 promotes degradation via deacetylation-linked ubiquitination, and circadian BMAL1/CLOCK transcription drives daily IKr oscillation.

    Evidence Dominant-negative Rab11 experiments; HDAC6 inhibition/siRNA with lysine mutagenesis; cardiomyocyte-specific Bmal1 knockout with ECG telemetry and promoter assays

    PMID:25701773 PMID:26152716 PMID:29355491

    Open questions at the time
    • Interplay between recycling, degradation, and circadian transcription not modeled quantitatively
    • Physiological signals triggering HDAC6-hERG interaction unknown
  11. 2017 High

    The cryo-EM structure of open-state hERG at 3.8 Å revealed the structural basis of drug promiscuity—an atypically small central cavity with four deep hydrophobic pockets—and provided a framework for understanding inactivation gating.

    Evidence Single-particle cryo-electron microscopy at 3.8 Å resolution

    PMID:28431243

    Open questions at the time
    • Closed-state and inactivated-state structures not yet resolved
    • Drug-bound structures needed to validate predicted binding modes
  12. 2018 High

    Voltage-sensor relaxation was identified as a key determinant of slow deactivation, with extracellular protons destabilizing the relaxed state via S3 acidic residues, linking pH sensitivity to gating mechanism.

    Evidence Gating current recordings combined with voltage-clamp fluorimetry and D509 mutagenesis

    PMID:30530765

    Open questions at the time
    • Molecular dynamics of voltage-sensor relaxation not modeled
    • In vivo relevance of pH-dependent gating modulation during ischemia not tested
  13. 2022 High

    A dual suppression-and-replacement gene therapy rescued both LQT2 and SQT1 phenotypes in iPSC-cardiomyocytes, demonstrating variant-independent therapeutic correction of KCNH2 channelopathies.

    Evidence shRNA + shRNA-immune cDNA in CRISPR-corrected isogenic iPSC-CMs with FluoVolt APD measurement

    PMID:36252106

    Open questions at the time
    • In vivo delivery and long-term expression durability not established
    • Efficacy in whole-heart arrhythmia models not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Inactivated-state and closed-state structures, the precise stoichiometry and arrangement of KCNE subunits in native IKr, and the in vivo therapeutic window for gene therapy or trafficking correction remain unresolved.
  • No inactivated-state or closed-state cryo-EM structure
  • Native KCNE subunit stoichiometry undetermined
  • In vivo gene therapy for KCNH2 channelopathies not yet demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 7
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-9609507 Protein localization 5 R-HSA-112316 Neuronal System 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-9909396 Circadian clock 1
Partners
CAV1FKBP38HSPA1AHSPA8KCNE1KCNE2KCNQ1YWHAE
Complex memberships
IKr channel complex (Kv11.1/KCNE2)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 HERG encodes the pore-forming subunit of the rapidly activating delayed rectifier K+ current (IKr) in cardiac myocytes; HERG-expressed channels in Xenopus oocytes recapitulate IKr biophysical properties including K+ selectivity, decline with depolarizations above 0 mV, and activation by extracellular K+. Heterologous expression in Xenopus oocytes, two-electrode voltage clamp Cell High 7736582
1995 HERG mutations (intragenic deletions, splice-donor mutations, and missense mutations) cause LQT2; HERG is strongly expressed in the heart and maps to chromosome 7q35-36. Linkage mapping, SSCP, DNA sequencing, Northern blot Cell High 7889573
1995 HERG encodes an inwardly rectifying K+ channel despite having the six-transmembrane architecture of depolarization-activated Kv channels; this inward rectification arises from rapid, voltage-dependent inactivation that attenuates K+ efflux at positive voltages. Xenopus oocyte expression, two-electrode voltage clamp Science High 7604285
1996 HERG inward rectification arises from rapid, voltage-dependent C-type-like inactivation that reduces conductance at positive voltages, providing a mechanism for suppression of cardiac arrhythmias during the action potential plateau. Mammalian cell expression, whole-cell patch clamp, gating analysis Nature High 8587608
1998 The HERG N-terminal domain is a eukaryotic PAS domain whose crystal structure resembles bacterial photoactive yellow protein; a hydrophobic surface 'hot spot' mediates binding to the channel body, and the PAS domain slows the rate of deactivation. X-ray crystallography, scanning mutagenesis, Xenopus oocyte electrophysiology Cell High 9845367
1999 MiRP1 (KCNE2) assembles with HERG to form channels that resemble native cardiac IKr in gating, unitary conductance, K+ regulation, and biphasic E-4031 inhibition; three MiRP1 missense mutations linked to LQT slow channel opening and accelerate closing. Co-expression in Xenopus oocytes and mammalian cells, patch clamp, single-channel recording, co-immunoprecipitation Cell High 10219239
1998 Novel LQT2 missense mutations (T474I, A614V, V630L) suppress HERG current by dominant-negative mechanisms; A614V and V630L additionally shift voltage dependence of inactivation to more negative potentials, enhancing inward rectification as a novel loss-of-function mechanism. Xenopus oocyte expression, two-electrode voltage clamp, co-injection experiments Circulation Research High 9721698
1999 Protons and Zn2+ directly interact with HERG channels, preferentially accelerating deactivation kinetics with higher apparent affinity than for tail current inhibition; extracellular acidification to pH 6.4 accelerates deactivation without shifting activation voltage dependence. Two-electrode voltage clamp in Xenopus oocytes, whole-cell patch clamp in L929 cells Biophysical Journal High 10388757
1999 The S4 voltage-sensing residue R534 of HERG functions as a voltage sensor: the R534C LQT2 mutation shifts voltage dependence of activation in the negative direction and accelerates both activation and deactivation. Xenopus oocyte expression, two-electrode voltage clamp, kinetic analysis Cardiovascular Research High 10690305
1999 ERG1 (Kv11.1/KCNH2) underlies the slow ('M-like') component of the M-current in NG108-15 neuroblastoma cells, demonstrating functional expression of hERG-related channels in non-cardiac neural tissue. PCR analysis of channel subunit expression, pharmacological dissection with E-4031/dofetilide, comparison of kinetics in expression studies Journal of Neuroscience Medium 10479678
2001 Thyrotropin-releasing hormone (TRH) modulates erg1/HERG K+ currents in GH3/B6 pituitary cells via a diffusible second messenger: TRH shifts voltage dependence of activation to more positive potentials and reduces maximal current amplitude; coinjection of MiRP1 with HERG does not influence TRH modulation. Perforated-patch whole-cell recording, cell-attached patch, cDNA injection into GH3/B6 cells, pharmacological dissection Journal of Physiology High 11283231
2002 ERG1 (KCNH2) and KCNQ1 co-immunoprecipitate with KCNE1 in horse heart tissue, demonstrating physical coassociation of these repolarizing channel subunits in native cardiac muscle. Immunoblotting, immunostaining, co-immunoprecipitation, patch-clamp electrophysiology American Journal of Physiology. Heart and Circulatory Physiology Medium 12063283
2003 Thapsigargin (SERCA inhibitor) rescues surface expression of trafficking-defective LQT2 mutations G601S and F805C without blocking HERG current, demonstrating that pharmacological correction of trafficking-deficient channels does not require channel block. Western blot, confocal immunofluorescence, whole-cell patch clamp, Brefeldin A treatment, HEK293 cell expression Journal of Biological Chemistry High 12837749
2003 Selective knockout of the ERG1 B isoform eliminates IKr in adult mouse ventricular myocytes; fetal myocytes show two deactivation time constants and the rapid component is absent in ERG1 B knockout, indicating ERG1 B is required for IKr expression in adult cardiac membranes. Homologous recombination knockout, patch clamp electrophysiology, ECG Molecular and Cellular Biology High 12612061
2003 The N588K gain-of-function mutation in the S5-P loop of HERG dramatically increases IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduces channel affinity for IKr blockers, causing short QT syndrome. Patch clamp electrophysiology, action potential measurements, pharmacological testing Circulation High 14676148
2004 PIP2 regulates HERG channel gating through a positively charged C-terminal segment (residues 883–894): neutralizing this region abolishes PIP2-dependent acceleration of activation kinetics and hyperpolarizing shifts in voltage dependence of activation, and nearly eliminates specific PIP2 binding, while inactivation regulation by PIP2 remains intact. Whole-cell patch clamp, inside-out patch recording, deletion/mutagenesis of HERG, radiolabeled PIP2 binding assay, rabbit ventricular myocyte α1A-adrenergic stimulation American Journal of Physiology. Heart and Circulatory Physiology High 15231497
2005 Ceramide causes ubiquitin-mediated lysosomal degradation of HERG, reducing surface expression; this effect is not due to changes in channel gating properties but is demonstrated by surface biotinylation, Western blot, immunocytochemistry, and association with lysosomes. Surface biotinylation, Western blot, immunocytochemistry, whole-cell patch clamp, HEK293 stable expression Journal of Cell Science High 16263765
2005 Pentamidine reduces hERG protein surface expression (not via acute channel block) at clinically relevant concentrations, causing QT prolongation; chronic exposure reduces hERG polypeptide levels and membrane intensity, as shown by Western blot and confocal microscopy. Patch clamp, Western blot, laser-scanning confocal microscopy, HEK293 stable cell line British Journal of Pharmacology High 15711592
2006 14-3-3ε binds to a PKA phosphorylation site in the HERG C-terminus and amplifies β-adrenergic stimulation of HERG channel activity; LQT2 C-terminal truncation mutations (G965X, R1014PfsX39, V1038AfsX21) lose the PKA site, preventing 14-3-3ε-mediated hyperpolarizing shift in voltage dependence and exerting dominant-negative effects. Co-expression in CHO cells, patch clamp, Western blot, computer simulation of action potential Human Molecular Genetics High 16923798
2006 Most LQT2 missense mutations (28 of 34 tested) reduce Kv11.1 function by a trafficking-deficient (class 2) mechanism, and this phenotype can be corrected by low temperature (27°C) or pharmacological agents (E4031, thapsigargin). Western blot (glycosylation shift assay), patch clamp, HEK293 cell expression of 34 mutants Circulation High 16432067
2007 FKBP38 (a membrane-integrated co-chaperone) interacts with HERG via co-immunoprecipitation and co-localization; siRNA knockdown of FKBP38 reduces HERG trafficking, and FKBP38 overexpression partially rescues the trafficking-defective LQT2 mutant F805C. Proteomics screen (myc-tagged HERG), co-immunoprecipitation, siRNA knockdown, confocal microscopy, Western blot, in cardiac (HL-1) and HEK293 cells Journal of Biological Chemistry High 17569659
2007 Kv11.1 (hERG1) protein localizes in cholesterol- and sphingolipid-enriched membrane fractions (lipid rafts) in canine ventricular myocytes and HEK293 cells; LQT2 mutant G601S-Kv11.1 is excluded from these fractions. Cholesterol depletion shifts voltage dependence of activation and accelerates deactivation, while cholesterol loading reduces voltage sensitivity and accelerates inactivation. Immunocytochemistry, sucrose density gradient fractionation, detergent and non-detergent methods, methyl-β-cyclodextrin cholesterol depletion/loading, patch clamp Channels High 18708743
2007 HERG co-immunoprecipitates more readily with KCNE1 than KCNE2 during biosynthesis; KCNE1 preferentially co-localizes with HERG in ER, Golgi, and plasma membrane, while KCNE2 preferentially accumulates at the cell surface and in extracellular compartments, with differential assembly determined by trafficking rates rather than intrinsic affinity differences. Co-immunoprecipitation, Brefeldin A trafficking block, ER-retention signal engineering, surface labeling, confocal immunofluorescence PLoS One Medium 17895974
2008 The K897T polymorphism in hERG1 creates an Akt phosphorylation site; PI3K/Akt signaling (normally stimulating K897 channels via PP5 dephosphorylation) instead inhibits T897 channels via Akt-mediated phosphorylation, predicting QT interval prolongation in carriers. Electrophysiology in pituitary cells, PI3K signaling pathway manipulations, bioinformatics identification of phosphorylation site PNAS Medium 18791070
2008 Caveolin-1 physically interacts with the HERG N-terminus (identified by yeast two-hybrid and confirmed by co-immunoprecipitation), negatively regulating HERG current amplitude and slowing tail current deactivation; lipid raft disruption or caveolin-1 knockdown increases HERG current. Yeast two-hybrid, co-immunoprecipitation, fluorescence immunocytochemistry, RNA interference, whole-cell patch clamp in HEK293/HERG cells Biochemistry and Cell Biology Medium 18923542
2009 Sustained PKA activation increases HERG protein abundance 2- to 4-fold within 24 h by accelerating the rate of HERG protein synthesis (not transcription and not trafficking rate); direct PKA phosphorylation of the nascent HERG protein is required for this effect. cAMP/forskolin treatment, PKA inhibitors, metabolic pulse-chase labeling, Western blot in HEK293 cells, patch clamp, quantification of synthesis vs. stability American Journal of Physiology. Heart and Circulatory Physiology High 19234087
2010 Hsp70 promotes hERG maturation and surface expression by suppressing ubiquitination, while Hsc70 counteracts Hsp70; heat shock switches mouse ERG from Hsc70 to Hsp70 association, increasing IKr and shortening action potential duration. LQT2 mutants with intracellular domain mutations bind Hsc70 with higher affinity than WT. Co-expression in HEK293 cells, co-immunoprecipitation, immunocytochemistry, siRNA knockdown of Hsc70, heat shock treatment of HL-1 cardiomyocytes, patch clamp Circulation Research High 21183741
2010 KvLQT1 and HERG physically interact through their C-termini (demonstrated by co-immunoprecipitation and surface plasmon resonance); pore-mutant KvLQT1 expression reduces HERG surface expression and IKr by ~70%, and conversely, HERG expression reduces IKs, revealing reciprocal downregulation mediated by C-terminal interactions. Co-immunoprecipitation, surface plasmon resonance, immunostaining, patch clamp in CHO stable cell lines American Journal of Physiology. Heart and Circulatory Physiology High 20833965
2012 N-terminally truncated hERG channels generated by translational reinitiation at Met124 following the Q81X premature stop codon escape NMD, co-assemble with full-length hERG, and exhibit increased deactivation rates and reduced outward current, consistent with disruption of N-terminal deactivation regulation. Minigene mRNA analysis, Western blot, site-specific mutagenesis, whole-cell patch clamp, action potential clamp, HEK293 expression Journal of Molecular and Cellular Cardiology High 22964610
2013 PIKfyve kinase (activated by PKB/Akt) increases hERG channel protein abundance at the cell membrane and hERG current in Xenopus oocytes; PKB/Akt further augments hERG activity in a PIKfyve-dependent manner. Dual electrode voltage clamp in Xenopus oocytes, confocal microscopy with antibody-chemiluminescence quantification, co-expression experiments Cellular Physiology and Biochemistry Medium 23735862
2014 Multiple cytoplasmic domain interactions regulate slow deactivation of Kv11.1: a specific charge-charge interaction between Arg56 of the PAS domain and Asp803 of the cNBH domain, plus interactions between the N-Cap and the C-linker domain, stabilize the open channel conformation. Mutant cycle analysis, patch clamp electrophysiology in HEK293 cells, systematic mutagenesis of interdomain contacts Journal of Biological Chemistry High 25074935
2014 In LQT2 transgenic rabbit cardiomyocytes, hyperphosphorylated RyRs (due to loss of PP1/PP2 from the RyR complex) generate enhanced SR Ca2+ leak, leading to aberrant late Ca2+ releases that increase forward-mode NCX1 current, slow repolarization, and promote EADs. Confocal Ca2+ imaging, Western blot, co-immunoprecipitation, β-adrenergic stimulation, CaMKII inhibition, computer simulation in transgenic LQT2 rabbit model Circulation Research High 25249569
2015 The cardiomyocyte molecular clock (BMAL1/CLOCK) directly transactivates the Kcnh2 promoter, driving circadian expression of Kcnh2; cardiomyocyte-specific Bmal1 deletion reduces IKr by ~50% and prolongs the rate-corrected QT interval during the resting phase. Inducible cardiomyocyte-specific Bmal1 knockout mice, qPCR, voltage clamp, promoter-reporter bioluminescence assay, ECG telemetry Heart Rhythm High 25701773
2015 Rab11 (but not Rab4) mediates recycling of internalized hERG channels back to the plasma membrane; interfering with Rab11 delays hERG recovery after low K+-enhanced internalization and reduces steady-state hERG expression and function. Patch clamp, Western blot, confocal imaging, Rab11 dominant-negative expression, proteinase K surface clearance assay, cycloheximide treatment, HEK293 cells Journal of Biological Chemistry High 26152716
2015 hERG channel expression is reduced by high glucose via inhibition of Hsp90 expression and disruption of its interaction with hERG, leading to activation of the unfolded protein response (UPR; ATF-6, calnexin upregulation) and trafficking inhibition; insulin rescues hERG expression under high-glucose conditions. Western blot, patch clamp, immunoprecipitation, HEK293 stable expression Cellular Physiology and Biochemistry Medium 26303164
2015 Probucol reduces hERG membrane expression by decreasing SGK1 expression, thereby reducing phosphorylation of Nedd4-2; dephosphorylated Nedd4-2 promotes ubiquitin-mediated hERG degradation. Carbachol rescues by activating alternative Nedd4-2 phosphorylation. Western blot, immunoprecipitation, patch clamp, pharmacological rescue in HEK293/hERG cells Drug Design, Development and Therapy Medium 26229434
2016 HDAC6 interacts with immature hERG protein, deacetylating key lysine residues (K116, K495, K757) to promote ubiquitination and degradation; HDAC6 inhibition (Tubastatin A or siRNA) increases hERG acetylation, reduces ubiquitination, stabilizes hERG, restores surface expression of trafficking-defective mutants G601S and R752W, and increases IKr. Co-immunoprecipitation, Western blot, siRNA knockdown, mutagenesis of lysine residues, immunochemistry, patch clamp in HEK293 and HL-1 cells Journal of Molecular and Cellular Cardiology High 29355491
2016 hERG1a C-terminus truncation mutants (G965X, R1014X) exert dominant-negative gating and trafficking defects only when co-expressed with both wild-type hERG1a and hERG1b, not when expressed alone; co-immunoprecipitation and FRET confirm physical association of mutant and wild-type subunits. Electrophysiology, co-immunoprecipitation, FRET in HEK293 cells and guinea pig cardiomyocytes Heart Rhythm Medium 26775140
2017 Cryo-EM structure of open-state hERG at 3.8 Å reveals depolarized voltage sensors, an open pore, an atypically small central cavity surrounded by four deep hydrophobic pockets (explaining drug promiscuity), and a subtle selectivity filter feature possibly correlating with fast inactivation. Cryo-electron microscopy at 3.8 Å resolution Cell High 28431243
2018 Laminar shear stress increases hERG whole-cell current by 30–40%, shifting activation to hyperpolarizing potentials, accelerating activation and recovery from inactivation, and slowing deactivation via the integrin/focal adhesion kinase pathway; this effect requires the PAS domain in hERG1a and is absent in hERG1b (which lacks the PAS domain) and PAS-domain LQT2 mutants. Whole-cell patch clamp under defined laminar shear stress, FAK-specific inhibitors, comparison of hERG1a vs. hERG1b and PAS mutants, HEK293T cells Journal of Biological Chemistry Medium 29305421
2018 Extracellular acidification destabilizes voltage sensor relaxation in hERG, causing an ~20-mV shift in voltage dependence of deactivation and accelerating deactivation kinetics; neutralization of D509 in S3 mimics the proton effect, identifying acidic S3 residues as countercharges that stabilize the relaxed (activated) voltage sensor state. Gating current recordings, voltage clamp fluorimetry of voltage sensor domain dynamics, mutagenesis of D509, varying extracellular pH Journal of General Physiology High 30530765
2020 Kcnh2 deficiency aggravates sepsis-induced cardiac dysfunction by inhibiting FAK/AKT signaling, upregulating FOXO3A and its pro-apoptotic targets; Kcnh2 activation rescues cardiac function. AKT activator or FOXO3A siRNA knockdown rescues the apoptotic phenotype caused by Kcnh2 loss. CLP/LPS rat model, Kcnh2+/- knockout, NS1643 activator treatment, echocardiography, Western blot, siRNA knockdown, survival analysis Cell Proliferation Medium 33263944
2022 A dual suppression-and-replacement KCNH2 gene therapy (shRNA knockdown + shRNA-immune cDNA in a single construct) normalizes pathologically prolonged APD90 in LQT2 iPSC-CMs (G604S, N633S) and pathologically shortened APD90 in SQT1 iPSC-CMs (N588K), demonstrating variant-independent rescue of both gain- and loss-of-function KCNH2 phenotypes. iPSC-derived cardiomyocytes, CRISPR-Cas9 isogenic controls, shRNA suppression, replacement cDNA, FluoVolt voltage dye APD measurement Circulation. Genomic and Precision Medicine High 36252106

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 2055 7736582
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
1995 A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1836 7889573
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2001 Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 1297 11136691
2006 hERG potassium channels and cardiac arrhythmia. Nature 1189 16554806
1995 HERG, a human inward rectifier in the voltage-gated potassium channel family. Science (New York, N.Y.) 1072 7604285
1999 MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1030 10219239
2000 Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 962 10973849
2005 Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science (New York, N.Y.) 881 15790807
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1994 A family of potassium channel genes related to eag in Drosophila and mammals. Proceedings of the National Academy of Sciences of the United States of America 824 8159766
2005 International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacological reviews 721 16382104
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 The inward rectification mechanism of the HERG cardiac potassium channel. Nature 647 8587608
2003 Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 601 14676148
2012 hERG K(+) channels: structure, function, and clinical significance. Physiological reviews 558 22988594
2005 Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart rhythm 452 15840476
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2004 Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 433 15367556
2017 Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG. Cell 413 28431243
2002 Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 412 11997281
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2009 Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart rhythm 371 19716085
1998 Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 366 9845367
2005 Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA 364 16414944
2007 Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 363 17210839
2006 Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation 340 16432067
2009 Common variants at ten loci influence QT interval duration in the QTGEN Study. Nature genetics 337 19305408
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2005 Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene 277 15750627
2008 The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacology & therapeutics 236 18616963
2020 hERG toxicity assessment: Useful guidelines for drug design. European journal of medicinal chemistry 227 32283295
2001 HERG K+ channels: friend and foe. Trends in pharmacological sciences 222 11339975
2003 A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovascular research 132 12829173
2008 The hERG K+ channel: target and antitarget strategies in drug development. Pharmacological research 121 18329284
2017 Development of Safe Drugs: The hERG Challenge. Medicinal research reviews 117 28467598
2004 Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. American journal of physiology. Heart and circulatory physiology 111 14975928
1999 Two types of K(+) channel subunit, Erg1 and KCNQ2/3, contribute to the M-like current in a mammalian neuronal cell. The Journal of neuroscience : the official journal of the Society for Neuroscience 107 10479678
2019 Computational determination of hERG-related cardiotoxicity of drug candidates. BMC bioinformatics 103 31138104
2005 Pentamidine reduces hERG expression to prolong the QT interval. British journal of pharmacology 101 15711592
2011 Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits. The Journal of physiology 94 22183728
1998 Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. Circulation research 92 9721698
2000 Long QT syndrome: cellular basis and arrhythmia mechanism in LQT2. Journal of cardiovascular electrophysiology 87 11196567
2008 Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction. Progress in biophysics and molecular biology 84 19027781
2003 Thapsigargin selectively rescues the trafficking defective LQT2 channels G601S and F805C. The Journal of biological chemistry 82 12837749
2001 Modulation of rat erg1, erg2, erg3 and HERG K+ currents by thyrotropin-releasing hormone in anterior pituitary cells via the native signal cascade. The Journal of physiology 81 11283231
2005 Expression and role of hERG channels in cancer cells. Novartis Foundation symposium 78 16050271
2007 Co-chaperone FKBP38 promotes HERG trafficking. The Journal of biological chemistry 77 17569659
2015 The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization. Heart rhythm 69 25701773
2002 Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart. American journal of physiology. Heart and circulatory physiology 69 12063283
2004 Selective expression of HERG and Kv2 channels influences proliferation of uterine cancer cells. International journal of oncology 68 15202000
2010 Eag and HERG potassium channels as novel therapeutic targets in cancer. World journal of surgical oncology 66 21190577
2005 Downregulation of the HERG (KCNH2) K(+) channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation. Journal of cell science 62 16263765
2004 Molecular analysis of PIP2 regulation of HERG and IKr. American journal of physiology. Heart and circulatory physiology 62 15231497
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2020 HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential. Biochimica et biophysica acta. Reviews on cancer 56 32135169
1999 Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. Human mutation 55 10220144
2013 Recent developments in computational prediction of HERG blockage. Current topics in medicinal chemistry 52 23675938
2010 A novel mutation in the KCNH2 gene associated with short QT syndrome. Journal of molecular and cellular cardiology 51 21130771
1998 Human ether-a-gogo related gene (HERG) K+ channels as pharmacological targets: present and future implications. Biochemical pharmacology 50 9714291
2007 Kv11.1 (ERG1) K+ channels localize in cholesterol and sphingolipid enriched membranes and are modulated by membrane cholesterol. Channels (Austin, Tex.) 48 18708743
2006 C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3epsilon. Human molecular genetics 48 16923798
1999 Proton and zinc effects on HERG currents. Biophysical journal 46 10388757
2003 Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia. Molecular and cellular biology 45 12612061
2013 PIKfyve sensitivity of hERG channels. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 44 23735862
2017 Natural products modulating the hERG channel: heartaches and hope. Natural product reports 43 28497823
2016 hERG quality control and the long QT syndrome. The Journal of physiology 43 26718903
2005 Squalene epoxidase encoded by ERG1 affects morphogenesis and drug susceptibilities of Candida albicans. The Journal of antimicrobial chemotherapy 43 15845783
2001 A novel sequence element is involved in the transcriptional regulation of expression of the ERG1 (squalene epoxidase) gene in Saccharomyces cerevisiae. European journal of biochemistry 43 11179957
2010 Reciprocal control of hERG stability by Hsp70 and Hsc70 with implication for restoration of LQT2 mutant stability. Circulation research 42 21183741
1999 Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2. Cardiovascular research 41 10690305
2017 Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer. Oncotarget 40 29423049
2001 Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome. British journal of pharmacology 39 11156564
2019 Rapid Characterization of hERG Channel Kinetics II: Temperature Dependence. Biophysical journal 37 31451180
2020 Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients. Biomolecules 35 32759882
2014 Multiple interactions between cytoplasmic domains regulate slow deactivation of Kv11.1 channels. The Journal of biological chemistry 35 25074935
2007 Differential association between HERG and KCNE1 or KCNE2. PloS one 35 17895974
2003 Terbinafine resistance in a pleiotropic yeast mutant is caused by a single point mutation in the ERG1 gene. Biochemical and biophysical research communications 35 12963042
2008 The human ERG1 channel polymorphism, K897T, creates a phosphorylation site that inhibits channel activity. Proceedings of the National Academy of Sciences of the United States of America 33 18791070
2013 Escitalopram block of hERG potassium channels. Naunyn-Schmiedeberg's archives of pharmacology 32 24045971
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2012 Voltage-dependent gating of HERG potassium channels. Frontiers in pharmacology 31 22586397
2009 PKA phosphorylation of HERG protein regulates the rate of channel synthesis. American journal of physiology. Heart and circulatory physiology 30 19234087
2020 Revealing Molecular Determinants of hERG Blocker and Activator Binding. Journal of chemical information and modeling 28 31880933
2008 hERG (KCNH2 or Kv11.1) K+ channels: screening for cardiac arrhythmia risk. Current drug metabolism 28 18991593
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2012 Toxin modulators and blockers of hERG K(+) channels. Toxicon : official journal of the International Society on Toxinology 27 22497787
2009 Comparative effects of sophocarpine and sophoridine on hERG K+ channel. European journal of pharmacology 26 19224706
2022 Suppression and Replacement Gene Therapy for KCNH2-Mediated Arrhythmias. Circulation. Genomic and precision medicine 25 36252106
2020 Kcnh2 mediates FAK/AKT-FOXO3A pathway to attenuate sepsis-induced cardiac dysfunction. Cell proliferation 25 33263944
2016 hERG 1a LQT2 C-terminus truncation mutants display hERG 1b-dependent dominant negative mechanisms. Heart rhythm 25 26775140
2015 High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25 26303164
2000 Regulation of the cardiac repolarizing HERG potassium channel by protein kinase A. Trends in cardiovascular medicine 25 11282296
2020 The Study on the hERG Blocker Prediction Using Chemical Fingerprint Analysis. Molecules (Basel, Switzerland) 24 32512802
2015 Getting to the heart of hERG K(+) channel gating. The Journal of physiology 24 25820318
2012 Pharmacophore modeling for hERG channel facilitation. Biochemical and biophysical research communications 24 22244872
2012 Early LQT2 nonsense mutation generates N-terminally truncated hERG channels with altered gating properties by the reinitiation of translation. Journal of molecular and cellular cardiology 24 22964610
2011 The KCNH2 gene is associated with neurocognition and the risk of schizophrenia. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 24 21936766
2017 Preclinical efficacy and safety of KCNH2-G628S gene therapy for postoperative atrial fibrillation. The Journal of thoracic and cardiovascular surgery 23 28676183
2015 Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency. Drug design, development and therapy 23 26543354
2010 Pore mutants of HERG and KvLQT1 downregulate the reciprocal currents in stable cell lines. American journal of physiology. Heart and circulatory physiology 23 20833965
2008 The regulation of the cardiac potassium channel (HERG) by caveolin-1. Biochemistry and cell biology = Biochimie et biologie cellulaire 23 18923542
2016 Allosteric Modulation of Kv11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias. Circulation. Arrhythmia and electrophysiology 21 27071825
2014 Berberine induces hERG channel deficiency through trafficking inhibition. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 21 25171176
2014 Co-production of ethanol and squalene using a Saccharomyces cerevisiae ERG1 (squalene epoxidase) mutant and agro-industrial feedstock. Biotechnology for biofuels 21 25298782
2010 Identification and expression analysis of kcnh2 genes in the zebrafish. Biochemical and biophysical research communications 21 20438705
2008 Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues. British journal of pharmacology 21 18604229
2004 Physical and functional interaction between integrins and hERG potassium channels. Biochemical Society transactions 21 15494025
2004 Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivation. Journal of molecular and cellular cardiology 21 15572050
2014 Effects of donepezil on hERG potassium channels. Brain research 20 25498859
2013 Indexing molecules for their hERG liability. European journal of medicinal chemistry 20 23727540
2004 Expression of the IKr components KCNH2 (rERG) and KCNE2 (rMiRP1) during late rat heart development. Experimental & molecular medicine 20 15365256
2010 Role of ERG1 isoforms in modulation of ERG1 channel trafficking and function. Pflugers Archiv : European journal of physiology 19 20574821
2018 Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation. The Journal of general physiology 18 30530765
2017 Why are most phospholipidosis inducers also hERG blockers? Archives of toxicology 18 28551711
2015 Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel. The Journal of biological chemistry 18 26152716
2022 Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes. International journal of molecular sciences 17 35806392
2021 Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia. Journal of cellular and molecular medicine 17 33939251
2018 Fluid flow modulates electrical activity in cardiac hERG potassium channels. The Journal of biological chemistry 17 29305421
2018 NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes. Biophysical journal 17 30173888
2016 Febrile temperature facilitates hERG/IKr degradation through an altered K(+) dependence. Heart rhythm 17 27321242
2015 Mechanisms underlying probucol-induced hERG-channel deficiency. Drug design, development and therapy 17 26229434
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2006 Protein distribution of Kcnq1, Kcnh2, and Kcne3 potassium channel subunits during mouse embryonic development. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 16 16463373
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2008 Kv11.1 channel subunit composition includes MinK and varies developmentally in mouse cardiac muscle. Developmental dynamics : an official publication of the American Association of Anatomists 15 18729211