Affinage

KCNH2

Voltage-gated inwardly rectifying potassium channel KCNH2 · UniProt Q12809

Length
1159 aa
Mass
126.7 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNH2 (hERG/Kv11.1) encodes the pore-forming alpha-subunit of the rapid delayed rectifier K+ current (IKr) that governs cardiac repolarization, and most loss-of-function disease alleles act not by disabling the channel pore but by blocking its delivery to the cell surface (PMID:16432067, PMID:12612061). Its hallmark slow deactivation is built from intramolecular contacts between the N-terminal N-Cap/PAS domain and the C-terminal cyclic-nucleotide-binding homology (cNBH) and C-linker domains, including a specific Arg56–Asp803 charge pair that stabilizes the open state (PMID:25074935), while the S4 arginine R534 serves as a voltage-sensor residue and the S4-S5 linker integrates cytoplasmic signals into gating rather than acting as a rigid lever (PMID:10690305, PMID:29270671). Native IKr requires co-assembly of the 1a and 1b isoforms: the 1b subunit is necessary for full current and normal action-potential duration, and the 1a-specific PAS domain confers slow deactivation (PMID:12612061, PMID:25453103). Surface expression depends on a chaperone and trafficking network in which Hsp70 stabilizes the channel and suppresses ubiquitination while Hsc70 promotes degradation, the co-chaperone FKBP38 and Hsp90 promote export, and Rab11B-dependent vesicular transport delivers channels from the ER, with the protein partitioning into cholesterol-rich lipid raft and T-tubular membranes (PMID:21183741, PMID:17569659, PMID:18708743, PMID:23864605). Trafficking-deficient (class 2) LQT2 mutants are recognized by the ER chaperones calnexin and calreticulin, trigger the unfolded protein response, and are cleared by the 26S proteasome, but can be rescued pharmacologically (E-4031, thapsigargin) or by reduced temperature (PMID:16432067, PMID:10753933, PMID:22242185, PMID:12837749). Channel activity is further tuned by beta-adrenergic/PKA signaling amplified through 14-3-3epsilon binding to the C-terminus, by extracellular protons that accelerate deactivation, and by Akt/PI3K signaling whose direction is reversed by the common K897T polymorphism (PMID:16923798, PMID:10388757, PMID:18791070). hERG associates with the KCNQ1/KCNE1 channel subunits in native cardiac tissue, and its expression is transcriptionally driven by Tbx20 (PMID:12063283, PMID:20833965, PMID:28049825).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Established that LQT2 missense mutations can suppress IKr through dominant-negative coassembly and, for some alleles, by shifting inactivation voltage dependence, defining distinct biophysical mechanisms of current loss.

    Evidence Two-electrode voltage clamp of WT/mutant co-injected Xenopus oocytes

    PMID:9721698

    Open questions at the time
    • Did not address whether suppression arises from gating versus trafficking defects
    • Limited to three pore/linker mutations
  2. 2000 High

    Showed that a dominant-negative LQT2 mutation lowers WT channel abundance by promoting recognition of misfolded heteromers and proteasomal turnover, shifting the disease paradigm toward protein quality control.

    Evidence Co-expression with myc-tagged WT, proteasome inhibition, temperature rescue, pulse-chase in mammalian cells

    PMID:10753933

    Open questions at the time
    • Specific ER recognition machinery not identified
    • Did not quantify residual surface current
  3. 2003 High

    Distinguished a trafficking-deficient (class 2) mechanism as correctable through the secretory pathway, showing pharmacological rescue restores surface expression and glycosylation via the Golgi.

    Evidence Confocal imaging, Western blot, electrophysiology with thapsigargin/E4031 and brefeldin A controls in HEK293

    PMID:12837749

    Open questions at the time
    • Molecular targets of thapsigargin/E4031 rescue distinct from acute block unresolved
    • Mutant-specific rescue differences unexplained
  4. 2003 Medium

    Defined the native subcellular localization and isoform requirement of IKr, placing ERG1 at the T-tubular system and showing the ERG1 B isoform is necessary for adult myocyte IKr.

    Evidence Immunoelectron microscopy in rat heart and isoform-selective knockout with patch clamp/ECG in mice

    PMID:12612061 PMID:14670813

    Open questions at the time
    • Isoform stoichiometry in human myocardium not established
    • Mechanism linking localization to repolarization efficacy inferred
  5. 2006 High

    Quantified the dominance of the trafficking-deficient mechanism across LQT2 alleles and identified C-terminal PKA-site/14-3-3epsilon coupling as a beta-adrenergic regulatory axis disrupted by truncation mutations.

    Evidence Systematic Western blot/expression of 34 mutations; CHO electrophysiology with dominant-negative co-expression

    PMID:16432067 PMID:16923798

    Open questions at the time
    • In vivo contribution of 14-3-3epsilon regulation to arrhythmia unquantified
    • Generalizability of rescue across all class-2 alleles incomplete
  6. 2007 Medium

    Identified specific chaperone components (FKBP38, Hsc70/Hsp90 system) and lipid raft/T-tubular partitioning as determinants of hERG surface delivery and biophysics.

    Evidence Proteomics, reciprocal Co-IP, siRNA, rescue, and membrane fractionation with cholesterol manipulation in HEK293/HL-1 and cardiomyocytes

    PMID:17569659 PMID:18708743

    Open questions at the time
    • Hierarchy among co-chaperones not fully ordered
    • Causal link between raft residence and native IKr gating not proven in vivo
  7. 2010 High

    Resolved opposing roles of Hsp70 and Hsc70 in hERG ubiquitination and stability and showed mutant channels bind Hsc70 more avidly, linking chaperone choice to degradation and demonstrating heat-shock rescue of IKr in cardiomyocytes.

    Evidence Co-IP, ubiquitination assays, siRNA, electrophysiology in HEK293 and HL-1 cells

    PMID:21183741

    Open questions at the time
    • E3 ligase coupling chaperone state to ubiquitination not identified here
    • Therapeutic feasibility of heat-shock induction untested in vivo
  8. 2012 Medium

    Connected trafficking-deficient mutants to ER chaperone surveillance and the unfolded protein response, and showed PAS-domain mutations form a biophysically distinct class often refractory to pore-blocker rescue.

    Evidence Co-IP with calnexin/calreticulin, ATF6/UPR readouts, in vitro PAS-domain unfolding, and trafficking/rescue assays

    PMID:22242185 PMID:22396785

    Open questions at the time
    • UPR contribution to arrhythmogenesis in vivo unestablished
    • Why PAS mutants resist pore-blocker rescue mechanistically unclear
  9. 2014 High

    Mapped the intramolecular N-Cap/PAS–cNBH/C-linker interactions governing slow deactivation and demonstrated that the 1b isoform and 1a PAS domain set native IKr magnitude and repolarization stability in human cardiomyocytes.

    Evidence Mutant cycle electrophysiology and shRNA/PAS-fragment manipulation in hiPSC-derived cardiomyocytes

    PMID:25074935 PMID:25453103 PMID:26775140

    Open questions at the time
    • Structural basis of N-Cap/cNBH contacts at atomic resolution not provided
    • Quantitative 1a:1b ratio in human heart unresolved
  10. 2017 Medium

    Defined transcriptional and gating-architecture contributions, showing Tbx20 directly drives KCNH2 expression and that the S4-S5 linker integrates cytoplasmic signals rather than acting as a rigid lever.

    Evidence Tbx20 overexpression/variant analysis in hiPSC-CMs and split-channel/MTS gating experiments

    PMID:28049825 PMID:29270671

    Open questions at the time
    • Broader transcriptional network controlling KCNH2 not mapped
    • Physiological signals relayed through the S4-S5 linker not enumerated
  11. 2020 Low

    Extended KCNH2 function beyond ion conduction by placing it upstream of FAK/AKT-FOXO3A cardiomyocyte survival signaling in a sepsis model.

    Evidence Kcnh2+/- rat model with echocardiography, Western blot, AKT activation, and FOXO3A siRNA rescue

    PMID:33263944

    Open questions at the time
    • Epistasis established by pharmacology without direct molecular interaction data
    • Whether channel conduction or a non-conducting role drives the effect unresolved
    • Not confirmed independently

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the chaperone/quality-control network, lipid environment, transcriptional control, and signaling inputs are integrated to set native IKr and how this can be therapeutically rescued in patient myocardium remains incompletely defined.
  • No unified in vivo model linking trafficking machinery to arrhythmia outcome
  • Atomic structures of full-length channel with regulatory domains absent from corpus
  • Allele-specific rescuability not predictable from sequence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3 R-HSA-162582 Signal Transduction 2 R-HSA-397014 Muscle contraction 2
Partners
CANXFKBP38HSPA1AHSPA8KCNE1KCNQ1RAB11BYWHAE
Complex memberships
IKr channel (hERG 1a/1b heteromer)KCNQ1/KCNE1 channel complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 The majority (28 of 34) of LQT2 missense mutations in Kv11.1 (hERG) cause loss of function through a trafficking-deficient (class 2) mechanism, trapping channels intracellularly. This trafficking-deficient phenotype could be corrected by incubation at reduced temperature (27°C) or with pore-blocking drugs E4031 or thapsigargin. Western blot analysis and heterologous expression in HEK293 cells for 34 LQT2 missense mutations Circulation High 16432067
1998 LQT2 missense mutations (T474I, A614V, V630L) in the S2-S3 linker and outer pore of HERG cause dominant-negative suppression of current. A614V and V630L additionally shift the voltage dependence of steady-state inactivation to negative potentials, enhancing inward rectification — a novel mechanism for HERG current suppression. Xenopus oocyte heterologous expression, two-electrode voltage clamp, co-injection of WT and mutant cRNA Circulation research High 9721698
2000 The dominant-negative LQT2 mutation A561V reduces wild-type HERG protein abundance by decreasing synthesis and increasing turnover. Co-assembly of wild-type subunits with A561V mutant occurs early in biogenesis, leading to recognition of misfolded channels and targeting for proteolysis via the 26S proteasome. Protein folding facilitation (30°C or glycerol) or proteasome inhibition (ALLN) partially rescues the dominant effect. Co-expression in mammalian cells, myc-tagged WT HERG tracking, proteasome inhibitor treatment, temperature rescue, Western blot The Journal of biological chemistry High 10753933
2003 Thapsigargin (a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase inhibitor) rescues surface membrane expression of trafficking-deficient LQT2 mutations G601S and F805C without blocking HERG channel current. Rescue requires an intact Golgi apparatus (blocked by brefeldin A) and produces complex glycosylation. The mechanism of rescue is pharmacologically distinct from the pore-blocker E4031 (which rescues G601S and N470D but not F805C). Confocal imaging, Western blot, electrophysiology, pharmacological rescue in HEK293 cells expressing LQT2 mutant channels The Journal of biological chemistry High 12837749
2007 FKBP38 (a membrane-integrated co-chaperone) interacts with HERG, co-localizes with it, and promotes its trafficking. siRNA knockdown of FKBP38 reduces HERG trafficking, and FKBP38 overexpression partially rescues the trafficking-deficient LQT2 mutant F805C. FKBP38 functions as part of the Hsc70/Hsp90 chaperone system for HERG. Proteomics screen, co-immunoprecipitation, confocal co-localization, siRNA knockdown, overexpression rescue in HL-1 and HEK293 cells The Journal of biological chemistry High 17569659
2010 Hsp70 and Hsc70 reciprocally control hERG stability. Hsp70 suppresses hERG ubiquitination and increases both immature and mature hERG levels and IKr; Hsc70 counteracts these effects. Disease-causing missense mutations in intracellular domains bind Hsc70 more avidly than WT channels. Knockdown of Hsc70 or heat shock (inducing Hsp70) prevents degradation of mutant hERG. Heat shock of HL-1 cardiomyocytes increased IKr and shortened action potential duration. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, electrophysiology, immunocytochemistry in HEK293 and HL-1 cells Circulation research High 21183741
2006 14-3-3epsilon binds to a PKA phosphorylation site in the HERG C-terminus and amplifies beta-adrenergic stimulation of HERG channel activity (hyperpolarizing shift in voltage dependence). Three LQT2 C-terminal truncation mutations (G965X, R1014PfsX39, V1038AfsX21) remove this PKA phosphorylation site; mutant channels bind 14-3-3epsilon but do not respond with a hyperpolarizing shift. These mutations exert dominant-negative behavior when co-expressed with WT channels. Co-expression in CHO cells, electrophysiology, dominant-negative co-expression experiments, computational action potential simulation Human molecular genetics High 16923798
2003 ERG1 (KCNH2) protein localizes primarily to the transverse tubular system and its entrance in adult rat ventricular and atrial myocytes, as determined by immunoelectron microscopy and confocal immunofluorescence. This restricted T-tubular localization positions ERG1 close to Ca2+ channels for maximal repolarizing effect. Confocal immunofluorescence microscopy and immunoelectron microscopy of rat heart tissue American journal of physiology. Heart and circulatory physiology Medium 14670813
2003 Selective knockout of the ERG1 B isoform in mice eliminates the rapid component of IKr deactivation (biexponential deactivation in WT adult myocytes; no IKr detected in ERG1 B(-/-) adult myocytes). ERG1 B knockout predisposes adult mice to episodic sinus bradycardia, establishing ERG1 B as necessary for IKr expression in the adult ventricular myocyte surface membrane. Homologous recombination knockout, whole-cell patch clamp of fetal and adult ventricular myocytes, ECG telemetry Molecular and cellular biology High 12612061
2014 hERG 1b is critical for cardiac IKr and normal repolarization. Specific shRNA knockdown of the 1b subunit in human iPSC-derived cardiomyocytes reduced IKr magnitude by ~50%, increased action potential duration, enhanced AP variability, and caused early afterdepolarizations. Expressing a fragment corresponding to the 1a-specific PAS domain (absent in 1b) to convert heteromers to 1a homomers recapitulated these effects. shRNA knockdown in human iPSC-derived cardiomyocytes, patch clamp, action potential measurements at physiological temperature Proceedings of the National Academy of Sciences of the United States of America High 25453103
2014 Multiple interactions between the N-terminal N-Cap/PAS domains and the C-terminal cNBH domain regulate Kv11.1 slow deactivation. Mutant cycle analysis identified a specific charge-charge interaction between Arg56 of the PAS domain and Asp803 of the cNBH domain, and an additional interaction between the N-Cap and cNBH domain. Positively charged N-Cap residues interact with negatively charged C-linker residues to stabilize the open state and slow deactivation. Mutant cycle analysis by electrophysiology in heterologous expression system The Journal of biological chemistry High 25074935
1999 Protons and Zn2+ directly interact with HERG channels and preferentially regulate the deactivation mechanism. Extracellular acidification at pHo 6.4 dramatically accelerates tail current deactivation without shifting activation voltage dependence. Kinetics effects occur at lower concentrations than current inhibition (pKa ~7.0 for deactivation kinetics vs 5.8 for tail current inhibition). Two-electrode voltage clamp in Xenopus oocytes and whole-cell patch clamp in L929 cells Biophysical journal Medium 10388757
1999 The S4 arginine residue R534 of HERG functions as a voltage sensor residue; the LQT2 mutation R534C shifts voltage-dependence of activation to negative potentials, accelerates activation and deactivation, and reduces steady-state inactivation, without causing dominant-negative suppression. Heterologous expression in Xenopus oocytes, whole-cell voltage clamp, kinetic analysis Cardiovascular research Medium 10690305
2001 TRH modulates erg1, erg2, erg3, and HERG K+ currents in anterior pituitary GH3/B6 cells via a diffusible second messenger, shifting voltage dependence of activation to more positive potentials and reducing maximal current amplitude. Co-injection of rat MiRP1 with HERG did not influence TRH-induced modulation. Cell-attached recording confirmed involvement of a diffusible second messenger. Perforated-patch whole-cell clamp, cDNA injection in GH3/B6 cells, pharmacological dissection of signaling pathways The Journal of physiology Medium 11283231
2007 Kv11.1 (hERG) protein localizes to cholesterol and sphingolipid-enriched membrane (lipid raft) fractions in both canine ventricular myocytes and HEK293 cells, as well as to the T-tubular sarcolemma. Depletion of membrane cholesterol with methyl-beta-cyclodextrin positively shifts activation voltage dependence and accelerates deactivation; cholesterol loading reduces the voltage dependence of activation and accelerates inactivation. The trafficking-deficient G601S mutant does not localize to lipid raft fractions. Detergent and non-detergent membrane fractionation, confocal immunocytochemistry, electrophysiology in HEK293 cells and native cardiomyocytes Channels (Austin, Tex.) Medium 18708743
2008 The KCNH2 polymorphism K897T creates a phosphorylation site for the Akt protein kinase. In cells with K897 (WT), PI3K/PP5 signaling stimulates K897 channels through dephosphorylation. In T897 cells, the same hormonal cascade inhibits T897 channels through Akt-mediated phosphorylation, reversing the direction of hormonal regulation of Kv11.1. Site-directed mutagenesis, electrophysiology, kinase inhibitor/activator pharmacology in heterologous expression system Proceedings of the National Academy of Sciences of the United States of America Medium 18791070
2007 HERG and KvLQT1 (KCNQ1) directly interact through their C-termini, as shown by co-immunoprecipitation and surface plasmon resonance analysis of isolated C-terminal domains. Expression of pore mutants or WT KvLQT1 in HERG-stable CHO cells reduces IKr by reducing HERG surface expression (~70% reduction); deletion of KvLQT1 NH2-terminus did not abolish downregulation. Co-immunoprecipitation, surface plasmon resonance, immunostaining, electrophysiology in stable CHO cell lines American journal of physiology. Heart and circulatory physiology Medium 20833965
2007 HERG co-precipitates more readily with KCNE1 than with KCNE2 during biogenesis. HERG co-localizes with KCNE1 in ER, Golgi, and plasma membrane, whereas KCNE2 is more abundant at the cell surface and in extracellular media. The differential HERG-KCNE association is determined primarily by distinct trafficking rates rather than differences in intrinsic binding affinity. Co-immunoprecipitation, confocal immunofluorescence, surface labeling, brefeldin A trafficking block, ER-retention signal engineering in heterologous expression system PloS one Medium 17895974
2013 Pharmacological correction (e.g., E-4031 or ranolazine) of trafficking-deficient LQT2 channel G601S promotes trafficking of channels stored in the transitional ER via a Rab11B-dependent pathway. 30-min drug exposure is sufficient for correction, and increased functional expression persists 4-5 h after washout. Dominant-negative Rab11B expression prevents pharmacological correction. Confocal analysis, co-expression with dominant-negative Rab11B, cycloheximide chase, pharmacological rescue with E-4031 and ranolazine in HEK293 cells American journal of physiology. Cell physiology Medium 23864605
2002 ERG1 (KCNH2) and KCNQ1 alpha-subunits co-immunoprecipitate with KCNE1 in horse heart tissue, providing direct evidence for co-association of these channel subunits in native cardiac tissue. Immunoblotting, co-immunoprecipitation, immunostaining, and patch-clamp in horse cardiac tissue American journal of physiology. Heart and circulatory physiology Medium 12063283
2012 Trafficking-deficient LQT2 mutants G572R-hERG and E637K-hERG interact more strongly with ER chaperones calnexin and calreticulin than WT-hERG, activate the unfolded protein response (UPR) by upregulating active ATF6, and are targeted for proteasomal degradation. Proteasome inhibition increases core-glycosylated forms of mutant hERG and enhances their interaction with calnexin/calreticulin. Co-immunoprecipitation, confocal microscopy, Western blot, proteasome inhibitor treatment in U2OS and HEK293 cells PloS one Medium 22242185
2015 High glucose reduces hERG channel expression and IKr through inhibition of channel trafficking, mediated by downregulation of Hsp90 and disruption of its interaction with hERG. High-glucose-mediated trafficking inhibition activates the unfolded protein response (ATF-6 and calnexin upregulation). Insulin (100 nM) rescues hERG expression reduced by high glucose. Western blot, immunoprecipitation, patch clamp, confocal microscopy in hERG-HEK293 cells Cellular physiology and biochemistry Medium 26303164
2012 LQT2-associated PAS domain mutations display molecular properties distinct from transmembrane region mutations: many do not cause trafficking deficiency and most trafficking-deficient PAS domain mutants are not rescued by a pore-blocking drug (E4031). PAS domain mutations reduce in vitro folding stability of the isolated PAS domain protein. Trafficking assay, temperature and drug rescue experiments, thermal and chemical unfolding fluorescence assays of isolated PAS domain proteins PloS one Medium 22396785
2012 A LQT2 nonsense mutation Q81X escapes nonsense-mediated mRNA decay and generates N-terminally truncated hERG channels by reinitiation of translation at Met124. These truncated channels have increased deactivation rates consistent with disruption of N-terminus-mediated deactivation regulation, and co-assemble with WT hERG to form heteromeric channels with increased deactivation. RNA analysis of hERG minigenes, Western blot, site-specific mutagenesis, voltage clamp electrophysiology, action potential clamp in HEK293 cells Journal of molecular and cellular cardiology Medium 22964610
2005 Pentamidine at clinically relevant concentrations (1-10 µM, 48h exposure) reduces hERG membrane expression and current density (36-85% reduction) by decreasing hERG protein levels at the surface membrane, rather than by direct acute channel block (acute IC50 ~252 µM, far above clinical exposure). This mechanism of trafficking reduction was established as the major basis for pentamidine-induced QT prolongation. Whole-cell patch clamp, Western blot, laser-scanning confocal microscopy in hERG-HEK293 cells and guinea pig ventricular myocytes British journal of pharmacology Medium 15711592
2017 The transcription factor Tbx20 directly enhances human KCNH2 gene expression and hERG currents (IhERG) and shortens action potential duration in human iPSC-derived cardiomyocytes. The LQT2-associated Tbx20 variant p.R311C fails to increase KCNH2 expression, leading to decreased IhERG and increased APD. Tbx20 does not modify other repolarization channel expression. Overexpression and variant analysis in hiPSC-CMs, patch clamp electrophysiology, action potential measurements Proceedings of the National Academy of Sciences of the United States of America Medium 28049825
2014 hERG 1a LQT2 C-terminus truncation mutants (G965X, R1014X) only exert dominant-negative gating and trafficking effects when co-expressed with hERG 1b, not when expressed alone with hERG 1a. Co-immunoprecipitation and FRET assays confirmed association of mutant and WT subunits. Electrophysiology, co-immunoprecipitation, FRET in HEK293 cells and guinea pig cardiomyocytes Heart rhythm Medium 26775140
2017 Gating of Kv11.1 (hERG) can be reconstructed from non-covalently linked voltage-sensing and pore modules (split channels), demonstrating that the S4-S5 linker does not function solely as a rigid mechanical lever. Progressive displacement of the split position within the S4-S5 linker modulates activation voltage dependence, deactivation rate, and voltage-sensor structural reorganization. The S4-S5 linker integrates cytoplasmic domain signals as part of the gating machinery. Split-channel electrophysiology with progressive displacement of split position, MTS accessibility assay of upper S4, voltage clamp in heterologous expression Pflugers Archiv : European journal of physiology Medium 29270671
2004 The common KCNH2 polymorphism K897T alters channel electrophysiology: K897T channels have lower current density, activate at more negative potentials, and inactivate and recover from inactivation faster than WT channels. P967L and R1047L channels are electrophysiologically indistinguishable from WT. All HERG channel types have similar sensitivity to cisapride block. Heterologous expression in HEK293 cells, Western blot, voltage-clamp electrophysiology American journal of physiology. Heart and circulatory physiology Medium 14975928
2004 hERG channels physically and functionally interact with beta1 integrin subunits in human neuroblastoma and leukaemia cells. Beta1 integrin activation causes long-lasting hERG channel activation; beta1 integrins and hERG1 co-precipitate, suggesting formation of a macromolecular signaling complex. hERG channel activity modulates integrin downstream signaling. Co-immunoprecipitation, electrophysiology, integrin activation assays in neuroblastoma and leukaemia cells Biochemical Society transactions Low 15494025
2013 Rab11B, a small GTPase, regulates Kv11.1 trafficking; dominant-negative Rab11B prevents pharmacological correction of the trafficking-deficient G601S LQT2 mutant from the transitional ER. Co-expression with dominant-negative Rab11B in HEK293 cells, confocal analysis, pharmacological rescue assays American journal of physiology. Cell physiology Medium 23864605
2015 Probucol reduces hERG channel membrane expression by decreasing SGK1 expression, leading to decreased phosphorylation of the E3 ubiquitin ligase Nedd4-2. Reduced Nedd4-2 phosphorylation results in enhanced hERG ubiquitination and degradation. Carbachol rescues hERG channels by restoring Nedd4-2 phosphorylation. Western blot, immunoprecipitation (ubiquitination assays), pharmacological rescue in hERG-HEK293 cells Drug design, development and therapy Low 26229434
2020 KCNH2 (Kcnh2) deficiency in a sepsis model activates the FAK/AKT-FOXO3A pathway: Kcnh2 knockout (Kcnh2+/-) rats show inhibition of FAK/AKT signaling, upregulation of FOXO3A and its downstream pro-apoptotic targets, and worsened cardiac dysfunction. Activation of AKT or siRNA knockdown of FOXO3A rescues the Kcnh2-deficiency phenotype, positioning Kcnh2 upstream of FAK/AKT-FOXO3A in cardiomyocyte survival signaling. Kcnh2+/- rat model, echocardiography, Western blot, AKT activator pharmacology, FOXO3A siRNA knockdown Cell proliferation Low 33263944
2013 PIKfyve, activated by PKB/Akt, upregulates hERG channel activity and increases hERG protein abundance in the cell membrane in Xenopus oocytes. PKB/Akt-resistant PIKfyve (S318A) does not augment hERG when combined with PKB, establishing PKB-mediated PIKfyve activation as upstream of hERG membrane expression. Xenopus oocyte co-expression, dual electrode voltage clamp, confocal microscopy with antibody-based surface quantification Cellular physiology and biochemistry Low 23735862

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 hERG potassium channels and cardiac arrhythmia. Nature 1205 16554806
2012 hERG K(+) channels: structure, function, and clinical significance. Physiological reviews 564 22988594
2006 Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation 343 16432067
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 235 32283295
2001 HERG K+ channels: friend and foe. Trends in pharmacological sciences 222 11339975
2008 The hERG K+ channel: target and antitarget strategies in drug development. Pharmacological research 122 18329284
2017 Development of Safe Drugs: The hERG Challenge. Medicinal research reviews 120 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
2005 Pentamidine reduces hERG expression to prolong the QT interval. British journal of pharmacology 101 15711592
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
2014 hERG 1b is critical for human cardiac repolarization. Proceedings of the National Academy of Sciences of the United States of America 86 25453103
2008 Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction. Progress in biophysics and molecular biology 85 19027781
2008 The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG). European heart journal 84 18222980
2003 Thapsigargin selectively rescues the trafficking defective LQT2 channels G601S and F805C. The Journal of biological chemistry 84 12837749
2000 The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. The Journal of biological chemistry 84 10753933
2003 Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovascular research 82 14613852
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
1998 HERG-like K+ channels in microglia. The Journal of general physiology 78 9607936
2007 Co-chaperone FKBP38 promotes HERG trafficking. The Journal of biological chemistry 77 17569659
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
2003 Expression and function of KCNH2 (HERG) in the human jejunum. American journal of physiology. Gastrointestinal and liver physiology 66 12736144
2003 EGF- and cell-cycle-regulated STAG1/PMEPA1/ERG1.2 belongs to a conserved gene family and is overexpressed and amplified in breast and ovarian cancer. Molecular carcinogenesis 64 14639658
2007 Expression and significance of HERG protein in gastric cancer. Cancer biology & therapy 60 17938585
2013 hERG channel function: beyond long QT. Acta pharmacologica Sinica 59 23459091
2020 HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential. Biochimica et biophysica acta. Reviews on cancer 58 32135169
2007 The hERG potassium channel as a therapeutic target. Expert opinion on therapeutic targets 56 17298291
2012 KCNH2 gene mutation: a potential link between epilepsy and long QT-2 syndrome. Journal of neurogenetics 54 22515331
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
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 46 12612061
1999 Proton and zinc effects on HERG currents. Biophysical journal 46 10388757
2017 Natural products modulating the hERG channel: heartaches and hope. Natural product reports 44 28497823
2013 PIKfyve sensitivity of hERG channels. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 44 23735862
2016 hERG quality control and the long QT syndrome. The Journal of physiology 43 26718903
2006 Cloning and characterization of the erg1 gene of Trichoderma harzianum: effect of the erg1 silencing on ergosterol biosynthesis and resistance to terbinafine. Fungal genetics and biology : FG & B 43 16466954
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 42 10690305
2003 Subcellular localization of the delayed rectifier K(+) channels KCNQ1 and ERG1 in the rat heart. American journal of physiology. Heart and circulatory physiology 41 14670813
2017 Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer. Oncotarget 40 29423049
2006 HERG trafficking and pharmacological rescue of LQTS-2 mutant channels. Handbook of experimental pharmacology 39 16610352
2014 hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia. European journal of pharmacology 38 24998878
2012 Changes in channel trafficking and protein stability caused by LQT2 mutations in the PAS domain of the HERG channel. PloS one 38 22396785
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 36 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
2020 hERG-Att: Self-attention-based deep neural network for predicting hERG blockers. Computational biology and chemistry 32 32531518
2013 Escitalopram block of hERG potassium channels. Naunyn-Schmiedeberg's archives of pharmacology 32 24045971
2017 Tbx20 controls the expression of the KCNH2 gene and of hERG channels. Proceedings of the National Academy of Sciences of the United States of America 31 28049825
2017 Gating mechanism of Kv11.1 (hERG) K+ channels without covalent connection between voltage sensor and pore domains. Pflugers Archiv : European journal of physiology 30 29270671
2016 hERG Blockade by Iboga Alkaloids. Cardiovascular toxicology 30 25636206
2013 Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum. American journal of physiology. Cell physiology 29 23864605
2020 Revealing Molecular Determinants of hERG Blocker and Activator Binding. Journal of chemical information and modeling 28 31880933
2012 Trafficking-deficient G572R-hERG and E637K-hERG activate stress and clearance pathways in endoplasmic reticulum. PloS one 28 22242185
2008 hERG (KCNH2 or Kv11.1) K+ channels: screening for cardiac arrhythmia risk. Current drug metabolism 28 18991593
2013 Current pharmacogenomic studies on hERG potassium channels. Trends in molecular medicine 27 23369369
2012 Toxin modulators and blockers of hERG K(+) channels. Toxicon : official journal of the International Society on Toxinology 27 22497787
2022 Suppression and Replacement Gene Therapy for KCNH2-Mediated Arrhythmias. Circulation. Genomic and precision medicine 26 36252106
2015 High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 26 26303164
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 Getting to the heart of hERG K(+) channel gating. The Journal of physiology 25 25820318
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 25 22964610
2017 Preclinical efficacy and safety of KCNH2-G628S gene therapy for postoperative atrial fibrillation. The Journal of thoracic and cardiovascular surgery 24 28676183
2012 RNA interference targeting E637K mutation rescues hERG channel currents and restores its kinetic properties. Heart rhythm 24 23022675
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
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
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
1999 Cloning and uterus/oviduct-specific expression of a novel estrogen-regulated gene (ERG1). The Journal of biological chemistry 21 10542259
2014 Effects of donepezil on hERG potassium channels. Brain research 20 25498859
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
2008 Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations. BMC medical genetics 19 18808722
2022 Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes. International journal of molecular sciences 18 35806392
2021 Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia. Journal of cellular and molecular medicine 18 33939251
2017 Why are most phospholipidosis inducers also hERG blockers? Archives of toxicology 18 28551711
2013 LQT2 nonsense mutations generate trafficking defective NH2-terminally truncated channels by the reinitiation of translation. American journal of physiology. Heart and circulatory physiology 18 23997099
2016 Schizophrenia-Associated hERG channel Kv11.1-3.1 Exhibits a Unique Trafficking Deficit that is Rescued Through Proteasome Inhibition for High Throughput Screening. Scientific reports 17 26879421
2015 Mechanisms underlying probucol-induced hERG-channel deficiency. Drug design, development and therapy 17 26229434
2014 KCNH2 polymorphism and methadone dosage interact to enhance QT duration. Drug and alcohol dependence 17 24875677
2000 Characterization of S818L mutation in HERG C-terminus in LQT2. Modification of activation-deactivation gating properties. FEBS letters 17 10996323
2024 Enhancing hERG Risk Assessment with Interpretable Classificatory and Regression Models. Chemical research in toxicology 16 38781421

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