Affinage

KCNQ1

Potassium voltage-gated channel subfamily KQT member 1 · UniProt P51787

Length
676 aa
Mass
74.7 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNQ1 (Kv7.1/KvLQT1) encodes the pore-forming α-subunit of a voltage-gated potassium channel that assembles with KCNE auxiliary subunits to generate tissue-specific currents critical for cardiac repolarization (IKs, with KCNE1), constitutive epithelial K⁺ conductance (with KCNE3), and K⁺ homeostasis in the inner ear, thyroid, and gastrointestinal tract (PMID:8900283, PMID:11220365, PMID:11120752, PMID:16314573). Channel activity is regulated by PKA anchored via AKAPs, PKC-triggered dynamin-dependent endocytosis requiring KCNE1-Ser102 phosphorylation, EGFR-mediated tyrosine phosphorylation, Nedd4-2 ubiquitylation counteracted by USP2, PIP2-dependent voltage sensor–pore coupling, and microtubule interactions through β-tubulin (PMID:11299204, PMID:21699843, PMID:20085748, PMID:22024150, PMID:25559286, PMID:18390900). Loss-of-function mutations cause long QT syndrome type 1 through dominant-negative suppression of IKs, ER retention with proteasomal degradation, or altered gating, while gain-of-function mutations cause familial atrial fibrillation or short QT syndrome (PMID:9312006, PMID:17053194, PMID:29532034, PMID:12522251, PMID:15159330). Beyond its channel function, KCNQ1 acts as an intestinal tumor suppressor by sequestering β-catenin at the plasma membrane in complex with E-cadherin, and the KCNQ1 locus harbors the imprinted antisense lncRNA Kcnq1ot1, which recruits PRC2 to regulate imprinting of neighboring genes including Cdkn1c (PMID:23975432, PMID:28373572, PMID:24395636, PMID:26100882).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Identifying KvLQT1's molecular partner resolved a long-standing question about the molecular identity of the cardiac IKs channel: KCNQ1 coassembles with KCNE1 (minK) to reconstitute a current matching native cardiac IKs.

    Evidence Two independent groups coexpressed KvLQT1 and minK in Xenopus oocytes with two-electrode voltage clamp

    PMID:8900282 PMID:8900283

    Open questions at the time
    • Stoichiometry of KCNQ1:KCNE1 complex not determined
    • Native cardiac complex composition not verified at protein level
  2. 1997 High

    Understanding how LQT1 mutations cause disease established two distinct pathomechanisms: most mutations exert dominant-negative suppression of wild-type IKs, while Jervell and Lange-Nielsen mutations abolish function without dominant-negative effects, explaining recessive versus dominant inheritance. The KCNQ1 locus was simultaneously shown to be tissue-specifically imprinted (maternally expressed in embryonal tissues, biallelic in heart).

    Evidence Coexpression of mutant and wild-type subunits in COS cells and Xenopus oocytes with electrophysiology; allele-specific expression analysis using SNPs across tissues

    PMID:9020845 PMID:9302275 PMID:9312006 PMID:9323054

    Open questions at the time
    • In vivo dominant-negative effect not quantified in cardiac tissue
    • Imprinting mechanism (cis-regulatory elements) not yet identified
  3. 1998 High

    Biophysical dissection of homomeric KCNQ1 revealed an intrinsic voltage-dependent inactivation process that is suppressed by KCNE1, explaining how the β-subunit transforms channel kinetics to produce the slowly activating, non-inactivating IKs.

    Evidence Detailed voltage-clamp protocols in Xenopus oocytes examining recovery from inactivation and deactivation

    PMID:9675180

    Open questions at the time
    • Structural basis of inactivation not resolved
    • Whether inactivation has physiological significance in native cardiomyocytes unknown
  4. 1999 High

    Discovery of the KvDMR1 imprinting control region and the Kcnq1ot1 antisense transcript within KCNQ1 introns established the locus as a major imprinting center, linking it to Beckwith-Wiedemann syndrome through loss of methylation and biallelic IGF2 expression.

    Evidence Methylation analysis of CpG island, RT-PCR allele-specific expression in BWS and control samples

    PMID:10393948

    Open questions at the time
    • Mechanism by which Kcnq1ot1 silences flanking genes not determined
    • Whether KvDMR1 methylation loss is cause or consequence of BWS not established
  5. 2000 High

    Mapping KCNE1 functional domains showed the transmembrane domain mediates subunit association while the C-terminal domain drives gating modulation, establishing a two-step model for β-subunit action. Separately, IKs block in ventricular wedge preparations showed that sympathetic stimulation—not IKs loss alone—creates the transmural dispersion of repolarization that triggers arrhythmias in LQT1.

    Evidence Deletion/chimeric minK constructs with Cd²⁺ block assay in oocytes; arterially perfused canine wedge with chromanol 293B and isoproterenol

    PMID:10716483 PMID:10962015 PMID:11120752

    Open questions at the time
    • Atomic-level KCNE1–KCNQ1 interface not resolved
    • In vivo confirmation of transmural dispersion mechanism in human LQT1 lacking
  6. 2001 High

    Identification of AKAP-mediated PKA anchoring to KCNQ1/KCNE1 complexes resolved how sympathetic (cAMP-dependent) regulation of IKs is achieved: without AKAPs, the channel complex is cAMP-insensitive. Simultaneously, KCNQ1/KCNE3 was shown to constitute the basolateral cAMP-activated K⁺ conductance in intestinal and airway epithelia.

    Evidence Coexpression with AKAP constructs, Ht31 peptide disruption, perforated-patch clamp; KCNE1 KO mice, native crypt patch-clamp, chromanol 293B pharmacology

    PMID:11220365 PMID:11299204 PMID:11527966

    Open questions at the time
    • Identity of the specific AKAP in native cardiomyocytes debated
    • Whether KCNE3 is the sole epithelial partner not fully resolved
  7. 2003 High

    The S140G gain-of-function mutation established that KCNQ1 dysfunction is bidirectional: enhanced IKs shortens atrial action potentials and causes familial atrial fibrillation. Additionally, KCNQ1 was found to physically interact with hERG via C-terminal domains, increasing hERG membrane expression and modifying its deactivation.

    Evidence Patch-clamp in oocytes and HEK cells for S140G; reciprocal co-IP in CHO cells and canine myocytes, GST pulldown, electrophysiology for KCNQ1-hERG interaction

    PMID:12522251 PMID:14585842

    Open questions at the time
    • Physiological significance of KCNQ1-hERG interaction for cardiac repolarization not established in vivo
    • Whether other gain-of-function mutations also cause AF unknown at this time
  8. 2005 High

    FRET microscopy and trafficking assays demonstrated that specific LQT1 mutations cause ER retention and dominant-negative suppression of wild-type KCNQ1 trafficking, establishing misfolding/trafficking failure as a distinct disease mechanism separate from channel gating defects. KCNQ1 was also shown essential for renal Na⁺/glucose reabsorption and gastric acid secretion in KO mice.

    Evidence GFP-tagged KCNQ1 in CHO-K1, C2C12, and COS-7 cells with FRET, confocal imaging, and patch-clamp; KCNQ1 KO mice with transepithelial transport measurements

    PMID:15935335 PMID:16314573 PMID:17053194

    Open questions at the time
    • Whether pharmacological chaperones can rescue ER-retained mutants untested
    • Relative contribution of trafficking versus gating defects across all LQT1 mutations unknown
  9. 2008 High

    Two discoveries revealed post-translational regulation of KCNQ1 abundance: ER-retained LQT1 mutants are ubiquitinated and degraded by proteasomes faster than wild-type, with KCNE1 stabilizing both; and KCNQ1 directly interacts with β-tubulin, with microtubule integrity required for PKA-dependent IKs augmentation but not basal IKs.

    Evidence Pulse-chase/proteasome inhibition/siRNA in T84 cells; yeast two-hybrid, co-IP in COS-7 and guinea pig cardiomyocytes, colchicine/taxol with permeabilized-patch clamp

    PMID:18390900 PMID:19114714

    Open questions at the time
    • E3 ligase responsible for ER-associated degradation of KCNQ1 not identified at this point
    • Mechanism by which microtubules gate PKA-dependent trafficking not determined
  10. 2011 High

    The ubiquitylation cycle controlling KCNQ1 surface density was completed: Nedd4-2 ubiquitylates and downregulates KCNQ1, while USP2 deubiquitylase opposes this and restores surface expression. Separately, PKC was shown to downregulate IKs through dynamin-dependent endocytosis triggered by KCNE1-Ser102 phosphorylation.

    Evidence Electrophysiology, co-IP, ubiquitination blots in oocytes and mammalian cells for USP2/Nedd4-2; dominant-negative dynamin, KCNE1-S102A mutant, confocal microscopy in CHO and neonatal myocytes for PKC/endocytosis

    PMID:21699843 PMID:22024150

    Open questions at the time
    • Whether USP2 regulates KCNQ1 in native cardiomyocytes unknown
    • Phosphatase that dephosphorylates KCNE1-S102 not identified
  11. 2013 High

    KCNQ1 was established as a tumor suppressor in the intestine: Kcnq1 loss in ApcMin mice dramatically increases tumor burden and promotes adenocarcinoma progression. Concurrently, oestrogen-induced KCNQ1 endocytosis was mapped to a clathrin/AP-2/Nedd4-2/PKCδ/AMPK pathway with Rab4/Rab11-mediated recycling, and LQT1 mutation carriers were shown to exhibit hyperinsulinemia, linking KCNQ1 to β-cell insulin secretion.

    Evidence Kcnq1 KO × ApcMin mice with tumor counting and organoid assays; Ussing chamber, biotinylation, co-IP in colonic cells; oral glucose tolerance and insulin measurements in LQT1 carriers

    PMID:23529131 PMID:23975432 PMID:24357532

    Open questions at the time
    • Mechanism by which KCNQ1 channel activity suppresses tumorigenesis (ion flux vs. scaffolding) not distinguished
    • Direct role of KCNQ1 in β-cell electrophysiology not reconstituted
  12. 2014 High

    The mechanism of Kcnq1ot1-mediated imprinting was resolved: the lncRNA recruits PRC2 via EZH2 and orchestrates a long-range chromatin loop between KvDMR1 and the Kcnq1 promoter; suppression of Kcnq1ot1 abolishes loop formation and Kcnq1 imprinting.

    Evidence RNA-guided chromatin conformation capture, ChIP for PRC2/EZH2, targeted Kcnq1ot1 knockdown, allele-specific expression

    PMID:24395636

    Open questions at the time
    • Whether additional chromatin remodelers beyond PRC2 are involved unknown
    • 3D chromatin architecture at the locus not mapped genome-wide
  13. 2015 High

    Voltage clamp fluorometry distinguished how KCNE1 and KCNE3 differentially modulate KCNQ1 gating: KCNE3 shifts voltage sensor S4 movement to extreme hyperpolarized potentials via electrostatic interactions (D54/D55–R228), rendering the channel constitutively open, while KCNE1 affects both S4 movement and the gate independently. PIP2 was identified as uniquely critical for KCNQ1 voltage sensor–pore coupling due to weak intrinsic electromechanical coupling.

    Evidence Voltage clamp fluorometry with S4 mutations and charge neutralization in oocytes; MD simulations with experimental mutagenesis

    PMID:25559286 PMID:26668384 PMID:28808020

    Open questions at the time
    • High-resolution structure of KCNQ1–PIP2 complex not available
    • PIP2 regulation in native cardiomyocytes not directly measured
  14. 2017 High

    KCNQ1 was shown to scaffold β-catenin at the plasma membrane via a complex with E-cadherin in colorectal cancer cells; KCNQ1 loss releases β-catenin to the cytosol, promoting Wnt signaling and loss of epithelial differentiation, while its promoter is reciprocally repressed by β-catenin:TCF-4, establishing a feedback loop.

    Evidence shRNA knockdown, co-IP, overexpression in CRC spheroids, chromanol 293B, luciferase reporter for TCF-4

    PMID:28373572

    Open questions at the time
    • Whether the tumor-suppressive effect requires ion conduction or only scaffolding not resolved
    • Relevance to non-colorectal cancers not established
  15. 2018 High

    Systematic analysis of 51 voltage sensor domain LQT1 variants revealed that over half cause VSD destabilization leading to mistrafficking and proteasomal degradation, with the S0 helix serving as a central organizing scaffold; six mechanistic categories of VSD dysfunction were defined.

    Evidence Automated electrophysiology, trafficking assay, proteasome inhibition, protein stability assays for all 51 variants

    PMID:29532034

    Open questions at the time
    • Whether variant-specific pharmacological rescue is feasible not tested
    • Structural basis of S0 scaffold function not determined at atomic resolution

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the high-resolution structure of KCNQ1 in complex with different KCNE subunits and PIP2; whether the tumor-suppressive function requires ion conduction versus protein scaffolding; the identity and regulation of KCNQ1 in pancreatic β-cell electrophysiology; and whether pharmacological chaperones can rescue trafficking-deficient LQT1 mutants in vivo.
  • No cryo-EM structure of full KCNQ1-KCNE1 complex with PIP2 reported in timeline
  • Ion conduction versus scaffolding in tumor suppression not dissected
  • Direct electrophysiological role of KCNQ1 in human β-cells not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1643685 Disease 5 R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-392499 Metabolism of proteins 3 GO:0005215 transporter activity 1
Partners
CTNNB1KCNE1KCNE2KCNE3KCNH2NEDD4LTUBBUSP2
Complex memberships
KCNQ1/KCNE1 (IKs channel)KCNQ1/KCNE3 (epithelial K+ channel)KCNQ1/β-catenin/E-cadherin

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 KCNQ1 (KvLQT1) coassembles with minK (IsK/KCNE1) to form the cardiac IKs slowly activating delayed-rectifier potassium channel; coexpression in Xenopus oocytes produces a current nearly identical to native cardiac IKs. Heterologous coexpression in Xenopus oocytes; two-electrode voltage clamp Nature High 8900282 8900283
1997 Most LQT1-associated KCNQ1 mutations act by dominant-negative suppression of wild-type KvLQT1/IKs current when co-expressed; a subset (e.g., JLN mutations) abolish function without dominant-negative effect, explaining the recessive inheritance pattern. Heterologous expression (COS cells, Xenopus oocytes), two-electrode and patch-clamp electrophysiology, co-expression with wild-type subunits The EMBO journal / Circulation / Human molecular genetics High 9302275 9312006 9323054
1997 IsK (KCNE1) not only changes KvLQT1 gating kinetics but also alters its ion selectivity when co-expressed. Heterologous co-expression in Xenopus oocytes, electrophysiology Human molecular genetics Medium 9302275
1998 Homomeric KvLQT1 channels exhibit a voltage-dependent inactivation process (distinct from classical C-type inactivation, independent of extracellular K+) that is largely absent in KvLQT1/minK heteromers; gating analysis supports a sequential scheme with at least two open states. Two-electrode voltage clamp in Xenopus oocytes, detailed gating analysis including recovery from inactivation and deactivation kinetics Biophysical journal High 9675180
1999 A maternally methylated CpG island (KvDMR1) within a KCNQ1 intron is associated with a paternally expressed antisense transcript (KvLQT1-AS/Kcnq1ot1) and acts as an imprinting control element; loss of methylation at KvDMR1 is associated with biallelic IGF2 expression in Beckwith-Wiedemann syndrome. RT-PCR allele-specific expression analysis, methylation analysis of CpG island across BWS and control samples Proceedings of the National Academy of Sciences of the United States of America High 10393948
2000 MinK C-terminal domain is necessary for gating modulation of KvLQT1 (slowing activation, increasing amplitude, removing inactivation), while the transmembrane domain is required for subunit association; the C-terminus alone is insufficient for modulation without the transmembrane domain interaction. Xenopus oocyte coexpression with deletion and chimeric MinK constructs; Cd2+ block assay to confirm association; electrophysiology The Journal of general physiology High 10962015
2000 Targeted disruption of Kvlqt1 in mice causes complete deafness with structural disruption of cochlear and vestibular end organs, and gastric mucous neck cell hyperplasia, demonstrating essential roles in inner ear development and gastric epithelium. Gene knockout mouse model; auditory testing; histochemistry; gastric pathology analysis The Journal of clinical investigation High 11120752
2001 AKAP proteins (AKAP79, mAKAP fragment, AKAP15/18) anchor PKA to the KvLQT1/IsK channel complex and are required for cAMP-dependent regulation of IKs; without AKAPs, the complex is insensitive to cAMP stimulation. Heterologous coexpression in mammalian cells; perforated-patch clamp; Ht31 peptide inhibition of PKA anchoring American journal of physiology. Heart and circulatory physiology High 11299204
2001 KCNQ1/KCNE3 complex forms the basolateral cAMP-activated K+ conductance in colonic and tracheal epithelial cells, providing the driving force for electrogenic Cl- secretion; KCNE3 (not KCNE1) is the relevant β-subunit in these epithelia. RT-PCR, Xenopus oocyte expression, patch-clamp on isolated crypts, pharmacological inhibition with chromanol 293B, KCNE1 knockout mice The Journal of membrane biology / The Journal of biological chemistry High 11220365 11527966
2003 The S140G gain-of-function mutation in KCNQ1 causes familial atrial fibrillation by enhancing IKs (KCNQ1/KCNE1) and KCNQ1/KCNE2 currents, reducing atrial action potential duration. Heterologous expression in Xenopus oocytes and HEK cells; patch-clamp electrophysiology; functional analysis of mutant vs. wild-type Science (New York, N.Y.) High 12522251
2003 KvLQT1 directly interacts with HERG α-subunit (co-immunoprecipitation in CHO cells and native cardiac tissue, GST pulldown with C-terminal HERG fragment), modifying HERG current deactivation kinetics and increasing HERG membrane expression approximately 2-fold. Co-immunoprecipitation, GST pulldown, immunolocalization, patch-clamp electrophysiology in CHO cells and canine ventricular myocytes The Journal of biological chemistry High 14585842
2003 KCNQ1 channel activity is sensitive to small changes in cell volume; this sensing is mediated through interactions between the channel N-terminus and the cytoskeleton, and is modulated (but not abolished) by KCNE1-3 subunits. Xenopus oocyte coexpression with aquaporin 1; cell volume manipulation; cytochalasin D treatment; N-terminal truncation mutants; electrophysiology The Journal of physiology Medium 12702742
2004 LQT1 mutations in the KCNQ1 N-terminal juxtamembranous region (Y111C, L114P, P117L) cause ER retention and failure to traffic to the plasma membrane; Y111C and L114P also suppress wild-type KCNQ1 trafficking through dominant-negative interaction in the ER. Confocal microscopy of GFP-tagged constructs; immunofluorescence; patch-clamp electrophysiology; expression in COS-7 cells and cardiomyocytes Circulation research High 17053194
2004 The KCNQ1 V307L gain-of-function mutation causes short QT syndrome by shifting half-activation potential and accelerating activation kinetics of IKs, leading to action potential shortening. Heterologous expression with patch-clamp; human action potential computer modeling Circulation Medium 15159330
2005 KCNQ1 is essential for Na+ and glucose absorption in proximal tubule and intestine, gastric acid secretion, and cAMP-induced jejunal Cl- secretion; in the kidney, KCNQ1 maintains driving force for electrogenic Na+ reabsorption during conditions of increased substrate load. Pharmacological inhibition (chromanol 293B) and KCNQ1 gene knockout mouse model; transepithelial transport measurements; serum and fecal ion measurements Proceedings of the National Academy of Sciences of the United States of America High 16314573
2005 LQT1 mutations cause abnormal KCNQ1 trafficking to the ER rather than the plasma membrane; certain mutants suppress wild-type channel trafficking via dominant-negative interaction in the ER, demonstrated by FRET microscopy. Biochemistry, patch-clamp electrophysiology, FRET microscopy; GFP-tagged KCNQ1 in CHO-K1 and C2C12 cells Cardiovascular research High 15935335
2007 Chromanol 293B binds within the inner pore vestibule of KCNQ1 involving hydrophobic interactions with S6 residues Ile337 and Phe340, and electrostatic interactions with a K+ ion in the selectivity filter; identified using KCNQ1/KCNQ2 chimeras and site-directed mutagenesis. Chimeric channel analysis, systematic mutagenesis, electrophysiology, computational docking model Molecular pharmacology High 17347319
2008 KCNQ1 directly interacts with β-tubulin (yeast two-hybrid, co-immunoprecipitation in COS-7 cells and guinea pig cardiomyocytes); microtubule integrity (not baseline IKs) is required for the IKs current response to PKA-dependent stimulation, while PKA phosphorylation of KCNQ1 and its association with Yotiao are maintained even when microtubules are disrupted. Yeast two-hybrid, co-immunoprecipitation, immunocytochemistry, permeabilized-patch clamp, colchicine/taxol pharmacology, phospho-specific antibodies Cardiovascular research High 18390900
2009 KCNE2 can substitute for KCNE1 in KCNQ1 channel complexes (dynamic partnership); KCNE1 shows turnover in the complex, and free KCNE peptides at the membrane can associate with existing KCNQ1 channels to modulate function; KCNE2 expression in adult guinea pig ventricular myocytes reduces native IKs density. Pulse-chase experiments, biotinylation assays, vesicle injection into KCNQ1-expressing oocytes, adenovirus-mediated expression in cardiomyocytes, immunolocalization, electrophysiology The Journal of biological chemistry High 19372218
2010 KCNQ1 interaction with hERG is mediated by their C-terminal domains (demonstrated by surface plasmon resonance and C-terminal deletion); this interaction is regulated by intracellular cAMP, with cAMP elevation reducing interaction by ~40%. Acceptor photobleach FRET in heterologous cells and primary cardiomyocytes; co-immunoprecipitation; surface plasmon resonance; C-terminal deletion constructs American journal of physiology. Heart and circulatory physiology High 23241319
2011 PKC activation (via phorbol ester) downregulates IKs by stimulating dynamin-dependent endocytosis of KCNQ1-KCNE1 complexes; this requires KCNE1 phosphorylation at Ser102, and functional dynamin is necessary for the effect. Patch-clamp electrophysiology; fluorescence microscopy; dominant-negative dynamin 2 (K44A); KCNE1-S102A mutant; transferrin endocytosis colocalization in CHO cells and neonatal mouse myocytes Heart rhythm High 21699843
2011 USP2 deubiquitylase counteracts Nedd4-2-mediated ubiquitylation and downregulation of KCNQ1; USP2 binds KCNQ1 independently of the PY motif, removes ubiquitin from KCNQ1, and restores surface expression and IKs amplitude. Electrophysiology in Xenopus oocytes and mammalian cells; Western blot for ubiquitination; co-immunoprecipitation; immunocytochemistry Heart rhythm High 22024150
2013 KCNQ1 functions as a tumor suppressor in the gastrointestinal tract; Kcnq1 knockout in ApcMin mice markedly increases intestinal tumor formation (especially proximal small intestine and colon), including progression to adenocarcinoma, and increases colon organoid formation, suggesting a role in intestinal crypt stem cell regulation. Conditional knockout mouse (Kcnq1 mutant crossed with ApcMin); intestinal tumor counting; colon organoid assay; microarray gene expression analysis Oncogene High 23975432
2013 In colonic epithelial cells, oestrogen (17β-oestradiol) promotes sustained inhibition of KCNQ1 by inducing clathrin-mediated, AP-2-dependent endocytosis of the channel followed by Rab4/Rab11-mediated recycling; this requires PKCδ and AMPK activation and Nedd4.2-mediated ubiquitylation of KCNQ1. Ussing chamber measurements; confocal immunofluorescence; co-immunoprecipitation (AP-2, Nedd4.2); pharmacological kinase inhibitors; biotinylation surface assays in HT29cl.19A colonic cells The Journal of physiology High 23529131
2013 Loss-of-function mutations in KCNQ1 in pancreatic β-cells cause hyperinsulinemia and reactive hypoglycemia in LQT1 patients, demonstrating that KCNQ1 regulates insulin secretion in β-cells. Oral glucose tolerance test; continuous glucose monitoring; insulin area-under-curve measurements; β-cell glucose sensitivity assays in LQT1 mutation carriers vs. matched controls Diabetes Medium 24357532
2014 The Kcnq1ot1 lncRNA orchestrates a long-range intrachromosomal loop between KvDMR1 and the Kcnq1 promoter that is required for maintenance of imprinting; Kcnq1ot1 recruits PRC2 via EZH2 to the locus; suppression of Kcnq1ot1 prevents loop formation and causes loss of Kcnq1 imprinting. RNA-guided chromatin conformation capture; ChIP for PRC2/EZH2; Kcnq1ot1 targeted knockdown; allele-specific expression analysis The Journal of cell biology High 24395636
2015 Paternal mutation at the Kcnq1 locus reduces pancreatic β-cell mass through epigenetic modulation: reduced Kcnq1ot1 expression leads to increased Cdkn1c (a cell cycle inhibitor) expression via altered histone modification at the Cdkn1c promoter in pancreatic islets, but only when the mutation is inherited paternally. Genetically modified mice with paternal vs. maternal transmission; quantitative PCR for Kcnq1ot1 and Cdkn1c; ChIP for histone marks at Cdkn1c promoter; β-cell mass measurement Proceedings of the National Academy of Sciences of the United States of America High 26100882
2015 KCNE3 acts primarily by shifting voltage sensor S4 movement to extreme hyperpolarized potentials (via electrostatic interaction of D54/D55 with R228 in S4), making KCNQ1/KCNE3 channels constitutively conducting in the physiological voltage range, while KCNE1 affects both the S4 movement and the gate independently. Voltage clamp fluorometry; S4 mutation to separate S4 movement from gate opening; PIP2 depletion; charge neutralization mutagenesis; electrophysiology in Xenopus oocytes Proceedings of the National Academy of Sciences of the United States of America High 26668384 28808020
2015 PIP2-dependent coupling between the voltage sensor domain and the pore is especially prominent in Kv7.1 (KCNQ1) due to weakened direct protein-protein interactions (electrostatic repulsion) between the S4-S5 linker and S6; molecular dynamics simulations identified a PIP2 binding site involving residues critical for this coupling. Molecular dynamics simulations; combined theoretical and experimental mutagenesis approaches; electrophysiology Scientific reports Medium 25559286
2017 KCNQ1 forms a complex with β-catenin and E-cadherin at the plasma membrane of well-differentiated colorectal cancer cells; KCNQ1 knockdown causes β-catenin redistribution from membrane to cytosol and loss of epithelial phenotype, while KCNQ1 overexpression traps β-catenin at the membrane; KCNQ1 promoter is repressed by β-catenin:TCF-4 in poorly differentiated cells. shRNA knockdown; co-immunoprecipitation; immunofluorescence colocalization; overexpression in CRC spheroids; chromanol 293B channel inhibition; transepithelial electrical resistance; luciferase reporter for TCF-4 binding Proceedings of the National Academy of Sciences of the United States of America High 28373572
2018 More than half of KCNQ1 loss-of-function mutations in the voltage sensor domain destabilize VSD structure, causing mistrafficking and proteasomal degradation; the S0 helix serves as a central scaffold to organize and stabilize the VSD; six mechanistic categories of VSD mutation-induced dysfunction were identified. Plasma membrane trafficking assay; proteasome inhibition; protein stability assays; automated electrophysiology for 51 VSD variants; cell surface expression for all variants Science advances High 29532034
2008 LQT1 mutations cause ER-retained KCNQ1 to be ubiquitinated and degraded by the proteasome more rapidly than wild-type KCNQ1 (t1/2 = 82 min vs. 113 min); KCNE1 co-expression stabilizes both wild-type and mutant (Y111C) KCNQ1; Derlin-1 co-immunoprecipitates with KCNQ1 but does not affect its degradation. Radiolabeling pulse-chase; Western blot for ubiquitination; proteasome inhibition; co-immunoprecipitation; siRNA knockdown in T84 cells The Journal of biological chemistry High 19114714
2010 KCNQ1/KCNE1 channels are present in lipid raft microdomains when KCNE1 or KCNE2 is the auxiliary subunit, while KCNE3-5 association directs KCNQ1 out of lipid rafts; KCNE subunits influence KCNQ1 membrane dynamics (as shown by FRAP). Sucrose gradient fractionation for lipid rafts; confocal immunofluorescence; FRAP experiments in HEK-293 cells Journal of cellular physiology Medium 20533308
1997 The KCNQ1 C-terminal domain contains important functional determinants; the R555C mutation in the C-terminal cytoplasmic region produces a functional channel with IsK but with strongly right-shifted voltage dependence of activation and accelerated deactivation, explaining the fruste phenotype in carriers. Heterologous expression in COS cells with electrophysiology; clinical genotype-phenotype correlation across 20 families The EMBO journal / Circulation High 9312006 9386136
2009 KCNQ1 is expressed in forebrain neuronal networks and brainstem nuclei in mice; dominant LQT1 mutations in KCNQ1 cause epilepsy in these mice, revealing dual arrhythmogenic potential in heart and brain. Transgenic mouse model carrying human LQT1 mutations; seizure monitoring; neuronal immunohistochemistry/localization studies Science translational medicine High 20368164
1997 KCNQ1 gene is imprinted in a tissue-specific manner: paternally imprinted (maternally expressed) in embryonal tissues but biallelic in cardiac muscle, explaining the lack of parent-of-origin effect in LQT syndrome despite imprinting. Allele-specific expression analysis using informative SNPs; BWS chromosomal rearrangement mapping Nature genetics High 9020845
2010 Kcnq1 knockout mice are hypothyroid with significantly lower T3/T4 plasma concentrations, demonstrating that Kcnq1 K+ channel activity is required for normal thyroid function, likely by maintaining membrane potential for electrogenic Na+/I- symporter activity. RT-PCR, confocal microscopy for expression; thyroid hormone measurements in Kcnq1-/- vs. wild-type mice; patch-clamp in FRTL-5 thyroid cells with chromanol inhibition Pflugers Archiv : European journal of physiology Medium 20978783
2010 Epidermal growth factor receptor (EGFR) kinase directly phosphorylates KCNQ1 protein, regulating IKs amplitude; EGFR inhibitors reduce IKs and decrease KCNQ1 tyrosine phosphorylation, while tyrosine phosphatase inhibition reverses this effect. Src-family kinases do not phosphorylate KCNQ1. Perforated patch-clamp; immunoprecipitation and Western blot for tyrosine phosphorylation; pharmacological inhibitors (genistein, AG556, PP2, orthovanadate) in HEK293 cells stably expressing KCNQ1/KCNE1 Biochimica et biophysica acta Medium 20085748
2000 I(Ks) block (LQT1 model) homogeneously prolongs action potential duration across ventricular cell types without increasing transmural dispersion of repolarization; addition of isoproterenol selectively prolongs action potential in M cells while shortening it in epicardial/endocardial cells, increasing transmural dispersion and triggering Torsade de Pointes. Arterially perfused canine left ventricular wedge preparation; simultaneous transmembrane action potential recording from three cell layers; pharmacological IKs block (chromanol 293B); beta-adrenergic stimulation Journal of the American College of Cardiology High 10716483

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1487 8900283
1996 K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1360 8900282
2000 Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 961 10973849
2003 KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science (New York, N.Y.) 786 12522251
2008 Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature genetics 580 18711367
2004 Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 449 15159330
1999 A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proceedings of the National Academy of Sciences of the United States of America 342 10393948
1997 Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Nature genetics 307 9020845
2000 Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. Journal of the American College of Cardiology 305 10716483
1997 KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 265 9386136
2009 Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Science translational medicine 238 20368164
2000 Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. The Journal of clinical investigation 233 11120752
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