Affinage

KCNQ4

Potassium voltage-gated channel subfamily KQT member 4 · UniProt P56696

Length
695 aa
Mass
77.1 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNQ4 encodes the voltage-gated potassium channel Kv7.4, which functions as a critical determinant of resting membrane potential in cochlear outer hair cells (OHCs), vestibular calyx afferents, rapidly adapting cutaneous mechanoreceptors, and vascular smooth muscle. In OHCs, KCNQ4 underlies the I(K,n) current; its loss causes chronic depolarization and progressive OHC degeneration, establishing the mechanism of autosomal dominant deafness DFNA2, where pore-region and C-terminal mutations act through dominant-negative ER retention, trafficking defects, or direct loss of conductance (PMID:10025409, PMID:16437162, PMID:20966080). Channel gating is positively regulated by PIP2 and Gβγ subunits (which act synergistically to increase open probability), PKA phosphorylation, and SGK1, while Ca²⁺/calmodulin inhibits activity through the S2-S3 intracellular loop and C-terminal IQ domains, and dynein-dependent retrograde trafficking through caveolin-1-containing membrane microdomains limits surface expression (PMID:25941381, PMID:27981364, PMID:33551832, PMID:33533890). In the vasculature, Kv7.4 predominantly forms heteromers with Kv7.5 stabilized by KCNE4 to regulate arterial tone, and its downregulation—partly through miR-153 targeting the KCNQ4 3′UTR—contributes to hypertension (PMID:24558103, PMID:26503181, PMID:27389411).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Identifying KCNQ4 as the molecular basis of DFNA2 deafness resolved how a single K⁺ channel mutation could dominantly silence OHC function: the G285C pore mutation abolishes currents and exerts a strong dominant-negative effect on wild-type subunits in heterotetramers.

    Evidence Cloning, heterologous patch-clamp, dominant-negative co-expression in Cell

    PMID:10025409

    Open questions at the time
    • Native OHC currents not yet recorded from mutant animals
    • Mechanism of dominant-negative action (ER retention vs. non-conducting tetramer) not distinguished
  2. 2000 High

    Immunolocalization established that KCNQ4 protein is restricted to the basal membrane of OHCs and to vestibular type I hair cell calyx terminals, identifying it as the molecular correlate of the I(K,n)/g(K,L) currents that set resting potential in these cells.

    Evidence Specific antibody immunofluorescence and electrophysiological correlation in PNAS

    PMID:10760300

    Open questions at the time
    • No genetic loss-of-function confirmation in vivo yet
    • Vestibular functional consequences not tested
  3. 2005 High

    Demonstrating that PKA phosphorylation shifts KCNQ4 activation by −10 to −20 mV and that Ca²⁺/calmodulin/calcineurin accelerates current run-down revealed the channel is under bidirectional kinase-phosphatase regulation, explaining how OHCs may tune K⁺ conductance dynamically.

    Evidence Patch-clamp in CHO cells with pharmacological PKA/calmodulin/calcineurin manipulation

    PMID:15660259

    Open questions at the time
    • Direct phosphorylation sites on KCNQ4 not mapped
    • In vivo relevance in OHCs not confirmed
  4. 2006 High

    Genetic disruption of KCNQ4 in mice proved that loss of I(K,n) causes chronic OHC depolarization leading to selective, progressive OHC degeneration while sparing inner hair cells, definitively establishing the cellular pathomechanism of DFNA2.

    Evidence Knockout and dominant-negative knock-in mice with ABR, patch-clamp, and histology in EMBO J

    PMID:16437162

    Open questions at the time
    • Whether pharmacological channel openers can rescue OHC degeneration in vivo unknown
    • Temporal window for intervention not defined
  5. 2007 High

    Discovery that alternative splicing of exons 9–11 shifts V₁/₂ by ~20 mV and that calmodulin differentially modulates splice variants revealed a mechanism for tissue-specific tuning of KCNQ4 gating properties.

    Evidence Heterologous expression with patch-clamp and calmodulin modulation assays in JBC

    PMID:17561493

    Open questions at the time
    • Which splice variants predominate in specific tissues (OHC vs. vasculature) not mapped
    • Heterotetramer stoichiometry of splice variants not determined
  6. 2009 High

    Finding that Caspr is required for clustering KCNQ4 at vestibular calyceal postsynaptic membranes identified the first molecular scaffold for KCNQ4 membrane retention, showing that septate-like junctions organize channel distribution.

    Evidence Caspr knockout mice with freeze-fracture EM and immunolabeling in J Neurosci

    PMID:19279247

    Open questions at the time
    • Whether Caspr-dependent clustering is required for cochlear OHC KCNQ4 unknown
    • Binding interface between Caspr and KCNQ4 not defined
  7. 2010 High

    Systematic analysis of six DFNA2 mutations revealed that ER retention—not just dominant-negative conductance block—is a common pathomechanism, and that aminoglycoside ototoxicity operates through PIP2 depletion to inhibit KCNQ4, establishing PIP2 as an obligatory gating cofactor.

    Evidence ER localization assays, combinatorial WT:mutant co-expression in HEK cells; PIP2 imaging and pharmacology in native OHCs

    PMID:20935082 PMID:20966080

    Open questions at the time
    • Whether PIP2 supplementation can rescue DFNA2 mutant channels in vivo unknown
    • Precise PIP2 binding site on KCNQ4 not structurally resolved
  8. 2011 High

    Localization of KCNQ4 to rapidly adapting mechanoreceptor nerve endings and demonstration that Kcnq4⁻/⁻ mice have elevated mechanosensitivity expanded the gene's functional role beyond hearing to somatosensory processing.

    Evidence Immunofluorescence, single-unit electrophysiology in knockout mice, human psychophysics in Nat Neurosci

    PMID:22101641

    Open questions at the time
    • Mechanism by which KCNQ4 modulates mechanoreceptor frequency response not defined
    • Whether DFNA2 patients have clinically significant touch phenotypes unknown
  9. 2011 High

    Demonstrating that Kv7.4 protein and mRNA are specifically reduced in arteries from hypertensive rats and mice established KCNQ4 as a vascular tone regulator whose downregulation contributes to hypertension.

    Evidence qPCR, western blot, isometric tension, patch-clamp in SHR and AngII-infused mice in Circulation

    PMID:21747056

    Open questions at the time
    • Whether restoring KCNQ4 expression is sufficient to normalize blood pressure not tested
    • Transcriptional mechanism of KCNQ4 downregulation in hypertension not identified
  10. 2013 High

    HSP90β was shown to rescue surface expression of trafficking-deficient DFNA2 mutants, but rescued channels remained non-conducting for pore mutations, proving that trafficking and conductance defects are mechanistically independent.

    Evidence Co-IP, HSP90β overexpression rescue, patch-clamp, and immunofluorescence in HEK293T

    PMID:23431407 PMID:23750663

    Open questions at the time
    • Whether HSP90 modulation can rescue hearing in vivo unknown
    • Chaperone interaction sites on KCNQ4 not mapped
  11. 2013 High

    Establishing that Kv7.4/Kv7.5 exist as native heteromers in vascular smooth muscle, differentially regulated by PKCα (which phosphorylates heteromers but not Kv7.4 homomers), explained subunit-specific signaling control of arterial tone.

    Evidence Proximity ligation assay, inducible PKCα system, patch-clamp in native VSMCs in JBC

    PMID:24297175 PMID:24558103

    Open questions at the time
    • PKCα phosphorylation sites on Kv7.5 within the heteromer not identified
    • Stoichiometry of Kv7.4:Kv7.5 subunits in native heteromers not resolved
  12. 2015 High

    Single-channel recordings proved that Gβγ subunits directly increase Kv7.4 open probability, and PIP2 depletion abolishes Gβγ stimulation—establishing that PIP2 and Gβγ are co-dependent obligatory activators of Kv7.4 gating.

    Evidence Excised-patch single-channel recording, PIP2 depletion, Gβγ inhibitors, PLA co-localization, renal artery tension in PNAS and Pflugers Arch

    PMID:25941381 PMID:27981364

    Open questions at the time
    • Structural basis for Gβγ-PIP2 synergy on Kv7.4 unknown
    • Whether Gβγ regulation operates on Kv7.4/Kv7.5 heteromers identically to homomers not tested
  13. 2015 High

    KCNE4 was identified as a vascular accessory subunit that co-localizes with Kv7.4 in mesenteric arteries and increases membrane expression; KCNE4 knockdown reduces surface Kv7.4 and augments vasoconstriction.

    Evidence PLA, co-expression patch-clamp, morpholino knockdown with tension recording in J Physiol

    PMID:26503181

    Open questions at the time
    • KCNE4 binding site on Kv7.4/Kv7.5 heteromers not mapped
    • Role of KCNE4 in cochlear KCNQ4 not investigated
  14. 2015 High

    Discovery of functional Kv7.4 channels in cardiac mitochondria, where activation depolarizes mitochondrial membrane potential and confers cardioprotection against ischemia-reperfusion, revealed an unexpected organellar role.

    Evidence Immunogold EM, mitochondrial fractionation, siRNA knockdown, Langendorff heart model in Cardiovasc Res

    PMID:26718475

    Open questions at the time
    • Mitochondrial targeting sequence or import mechanism for Kv7.4 not identified
    • Whether mitochondrial Kv7.4 is relevant to OHC survival unknown
  15. 2016 High

    miR-153 was shown to directly target the KCNQ4 3′UTR, providing a post-transcriptional mechanism for Kv7.4 downregulation in hypertensive arteries where mRNA levels are preserved but protein is reduced.

    Evidence Luciferase 3′UTR reporter, miR transfection into mesenteric arteries, tension recording in Cardiovasc Res

    PMID:27389411

    Open questions at the time
    • Whether anti-miR-153 therapy normalizes blood pressure in vivo not tested
    • Other miRNAs targeting KCNQ4 not surveyed
  16. 2019 High

    Crystal structure of Ca²⁺/CaM bound to KCNQ4 C-terminal helices A and B revealed a lobe-switching mechanism: apo-CaM C-lobe engages the B domain, and Ca²⁺ binding recruits the N-lobe, providing the first structural framework for Ca²⁺-dependent channel inhibition.

    Evidence X-ray crystallography, ITC, MST, HSQC NMR in JBC

    PMID:30808708

    Open questions at the time
    • Full-length channel structure with CaM not available
    • How C-terminal CaM binding communicates to the gate not structurally resolved
  17. 2021 High

    Mutagenesis of the S2-S3 intracellular loop identified specific residues (C156, C157, C158, R159, R161) through which Ca²⁺/CaM inhibits Kv7.4, with the EF3 hand of CaM controlling Ca²⁺-dependent regulation—completing the identification of channel-side determinants of CaM-mediated inhibition.

    Evidence Systematic mutagenesis of S2-S3 loop and CaM EF hands, patch-clamp in Frontiers Physiol

    PMID:33551832

    Open questions at the time
    • Whether S2-S3 loop directly contacts CaM or acts allosterically not structurally resolved
    • Functional relevance of this regulation in OHCs not confirmed
  18. 2021 High

    Dynein-dependent retrograde trafficking via a C-terminal dynein-binding site was identified as a mechanism controlling Kv7.4 surface density in vascular smooth muscle; caveolin-1 interaction within cholesterol-rich microdomains organizes this retrieval pathway.

    Evidence PLA, co-IP, mass spectrometry, ciliobrevin D inhibition, cholesterol depletion, morpholino knockdown in J Gen Physiol

    PMID:33533890

    Open questions at the time
    • Dynein-binding motif on KCNQ4 C-terminus not precisely mapped
    • Whether dynein-based trafficking operates in OHCs or neurons unknown
  19. 2022 High

    In vivo CRISPR/Cas9 disruption of the dominant-negative Kcnq4 W276S allele in OHCs improved auditory thresholds, providing proof-of-concept for allele-specific gene therapy for DFNA2.

    Evidence Dual AAV-CRISPR in vivo editing, ABR, DPOAE, thallium imaging in Theranostics

    PMID:35265220

    Open questions at the time
    • Long-term durability of hearing rescue not established
    • Off-target editing effects not comprehensively assessed
    • Whether approach generalizes to other DFNA2 mutations not tested
  20. 2022 Medium

    Truncated KCNQ4 variants lacking the tetramerization domain cause cytotoxicity independent of dominant-negative effects, revealing a gain-of-toxic-function pathomechanism distinct from classical DFNA2 trafficking or conductance loss.

    Evidence Heterologous expression of truncation mutants, viability assays, autophagy inducer rescue in Dis Model Mech

    PMID:34622280

    Open questions at the time
    • Whether truncation-induced cytotoxicity occurs in native OHCs in vivo not confirmed
    • Toxic species (misfolded monomer vs. aggregate) not identified
    • Single lab, heterologous system only

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length cryo-EM or crystal structure of the Kv7.4 tetramer—ideally with CaM, PIP2, and Gβγ bound—is needed to explain how these obligatory co-regulators synergistically gate the channel, and whether trafficking-deficient DFNA2 mutants adopt distinct misfolded conformations rescuable by pharmacological chaperones.
  • No full-length Kv7.4 structure available
  • Pharmacological chaperone strategy for DFNA2 not developed
  • Mitochondrial targeting mechanism completely unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 7 GO:0005739 mitochondrion 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-9709957 Sensory Perception 5 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4
Partners
CALM1CAV1CNTNAP1DYNC1H1GNB1HSP90AB1KCNE4KCNQ5
Complex memberships
Kv7.4 homotetramerKv7.4/KCNE4 complexKv7.4/Kv7.5 heterotetramer

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 KCNQ4 is expressed in cochlear outer hair cells at the basal membrane; a pore-region mutation (G285C) abolishes K+ currents of wild-type KCNQ4 and exerts a strong dominant-negative effect on co-expressed wild-type channels, establishing the mechanism of dominant deafness. Cloning, heterologous expression, patch-clamp electrophysiology, dominant-negative co-expression assay Cell High 10025409
2000 KCNQ4 protein localizes to the basal membrane of cochlear outer hair cells and is restricted to type I vestibular hair cells and afferent calyx nerve endings; multiple lines of evidence identify KCNQ4 as the molecular correlate of the I(K,n)/g(K,L) currents active at resting potentials in outer and type I hair cells. Specific antibody immunolocalization, electrophysiological correlation, subcellular fractionation/immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 10760300
2006 Genetic disruption or dominant-negative KCNQ4 mutation in mice abolishes the I(K,n) current of outer hair cells, causing chronic OHC depolarization that impairs sound amplification and leads to selective, progressive OHC degeneration; inner hair cells remain mostly intact. Knockout and knock-in mouse models, auditory brainstem response, patch-clamp electrophysiology, histology The EMBO journal High 16437162
2011 KCNQ4 is expressed in peripheral nerve endings of rapidly adapting hair follicle and Meissner corpuscle mechanoreceptors; Kcnq4-/- mice and DFNA2-mutation knock-in mice show elevated mechanosensitivity and altered frequency response specifically in rapidly adapting (but not slowly adapting) mechanoreceptor afferents, establishing KCNQ4 as a molecular regulator of touch sensitivity. Immunofluorescence of human/mouse cutaneous tissue, single-unit afferent electrophysiology in Kcnq4-/- and knock-in mice, human vibrotactile psychophysics Nature neuroscience High 22101641
2013 In vestibular organs, KCNQ4 (and KCNQ5) reside postsynaptically in calyx-forming neurons, not in the innervated hair cells; Kcnq4-/- and double-mutant mice display altered vestibulo-ocular reflexes indicating KCNQ4 contributes to vestibular function via postsynaptic K+ removal and modulation of synaptic transmission. Kcnq4-/- and dominant-negative knock-in mouse models, immunofluorescence, whole-cell patch clamp of vestibular hair cells, vestibulo-ocular reflex measurements The Journal of biological chemistry High 23408425
2007 Alternative splicing of KCNQ4 exons 9-11 in the C-terminal membrane-proximal region profoundly alters voltage-dependent activation (shifting V1/2 by ~20 mV) and functional surface expression; splice variants form heterotetramers, and calmodulin differentially modulates them through variant-specific calmodulin-binding domains. Heterologous expression, patch-clamp electrophysiology, dominant-negative co-expression, calmodulin modulation assays The Journal of biological chemistry High 17561493
2007 A DFNA2-causing pore-region mutation (G296S) impairs KCNQ4 by drastically reducing cell-surface expression (trafficking defect) and, secondarily, abolishing channel function; the G296S mutant exerts dominant-negative effects on wild-type KCNQ4 surface expression when co-expressed. Xenopus oocyte electrophysiology, HA-tagged surface expression assay in NIH-3T3 cells, co-expression dominant-negative analysis Human genetics High 18030493
2010 Intracellular aminoglycosides inhibit the KCNQ4-mediated I(K,n) current in outer hair cells by depleting phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2); extracellular aminoglycosides enter OHCs via an apical pathway and produce the same PI(4,5)P2-dependent inhibition with potency correlating with known ototoxic potential. KCNQ channel openers rescue I(K,n) from aminoglycoside inhibition. Whole-cell patch-clamp in rat OHCs, PI(4,5)P2 fluorescence imaging, pharmacological PI(4,5)P2 manipulation, recombinant KCNQ channel expression Molecular pharmacology High 20935082
2010 Five DFNA2 pore-region point mutations (L274H, W276S, L281S, G285C, G296S) and the C-terminal mutant G321S cause ER retention of KCNQ4 protein; co-expression of wild-type and mutant subunits reduces currents in a manner explicable by dependence of mutant surface expression on wild-type subunits, not simply by tetrameric dominant-negative stoichiometry. Heterologous expression in HEK cells, immunofluorescence for ER localization, patch-clamp electrophysiology, combinatorial wild-type:mutant ratio experiments The Journal of biological chemistry High 20966080
2005 PKA phosphorylation of KCNQ4 shifts its voltage of half-maximal activation by ~-10 to -20 mV; co-expression with the OHC motor protein prestin shifts activation a further -15 mV; elevated intracellular Ca2+ accelerates current run-down via calmodulin and calcineurin, which PKA prevents. Whole-cell patch clamp in CHO cells, pharmacological PKA activation/inhibition, co-expression with prestin, calmodulin/calcineurin inhibitors Pflugers Archiv : European journal of physiology High 15660259
2006 All five KCNE beta-subunits are expressed in outer hair cells and co-assembly with KCNQ4 in Xenopus oocytes modulates KCNQ4 voltage dependence, protein stability, and ion selectivity. The JLNS-associated KCNE1(D76N) mutation impairs KCNQ4 function, whereas the Romano-Ward KCNE1(S74L) does not. RT-PCR from OHC mRNA, Xenopus oocyte co-expression, two-electrode voltage clamp Cellular physiology and biochemistry Medium 16914890
2005 SGK1 kinase increases KCNQ4 current amplitude by ~67% and attenuates prepulse-dependent current enhancement in Xenopus oocytes; a putative SGK1 phosphorylation consensus sequence in KCNQ4 is required, as mutations of this Ser residue reduce SGK1 sensitivity. Xenopus oocyte co-expression, two-electrode voltage clamp, mutagenesis of putative phosphorylation site Cellular physiology and biochemistry Medium 16301825
2013 HSP70 and HSP90 chaperones interact with KCNQ4 (confirmed by reciprocal co-immunoprecipitation); HSP90α and HSP90β have opposing effects on KCNQ4 cellular levels; HSP40, HSP70, and HOP facilitate KCNQ4 biogenesis while CHIP (E3 ubiquitin ligase) promotes degradation. Over-expression of HSP90β improves cell-surface expression of trafficking-deficient KCNQ4 mutants L274H and W276S. Proteomics, reciprocal co-immunoprecipitation, RNAi knockdown/overexpression, surface expression assays (immunofluorescence, western blot) PloS one High 23431407
2013 Decreased KCNQ4 surface expression and direct impairment of channel conductance are two distinct mechanisms underlying DFNA2 mutations; overexpression of HSP90β restores surface expression of L281S, G296S, and G321S mutants but does not rescue K+ current, confirming independent trafficking and conductance defects. Immunofluorescence microscopy, western blot, patch-clamp electrophysiology, HSP90β overexpression rescue assay in HEK293T cells Journal of cellular and molecular medicine High 23750663
2009 Caspr (contactin-associated protein) is required for clustering KCNQ4 at the postsynaptic membrane of calyceal synapses on vestibular type I hair cells; in Caspr knockout mice KCNQ4 fails to cluster and is diffusely distributed along the calyceal membrane, demonstrating that a septate-like junction provides structural support for KCNQ4 retention. Freeze-fracture electron microscopy, immunolabeling, Caspr knockout mouse analysis The Journal of neuroscience High 19279247
2004 KCNQ4 channels expressed in HEK293 cells are activated by cell swelling and inhibited by shrinkage, contributing significantly to regulatory volume decrease; under isoosmotic conditions, PKA, PKC, G-protein activation, and reduced intracellular Ca2+ modulate channel activity, but these pathways do not account for swelling-induced activation. Whole-cell patch clamp in HEK293 cells under osmotic challenge, pharmacological pathway inhibition Biochimica et biophysica acta Medium 14757214
2011 In primary and spontaneously hypertensive rats, KCNQ4 mRNA and Kv7.4 protein are specifically reduced (~3.7-fold mRNA, ~50% protein) in aorta and mesenteric arteries, and Kv7 channel function (relaxation, K+ current augmentation) is dramatically impaired; the same Kv7.4 downregulation occurs in angiotensin II-infused hypertensive mice. qPCR, western blot, isometric tension recording, patch-clamp of isolated smooth muscle cells, pharmacological Kv7 activators/blockers Circulation High 21747056
2012 siRNA knockdown of KCNQ4 (~60% reduction of Kv7.4 protein) in rat renal arteries attenuates isoproterenol-induced relaxation, demonstrating that Kv7.4 channels mediate β-adrenoceptor-dependent vasodilation in the renal vasculature. siRNA knockdown, isometric tension recording, quantitative PCR, immunohistochemistry Hypertension High 22353613
2014 Kv7.4 and Kv7.5 proteins exist predominantly as functional heterotetramers (not homomers) in cerebral arteries as demonstrated by proximity ligation assay; siRNA knockdown of KCNQ4 (but not KCNQ5) attenuates CGRP-induced vasodilation, whereas both KCNQ4 and KCNQ5 siRNAs affect myogenic constriction. Proximity ligation assay, siRNA knockdown, isometric and isobaric myography Arteriosclerosis, thrombosis, and vascular biology High 24558103
2013 Kv7.4/Kv7.5 heteromers are endogenously expressed in vascular smooth muscle cells (confirmed by proximity ligation assay); PKCα activation is sufficient to suppress endogenous Kv7 currents; PKC phosphorylates Kv7.5 and Kv7.4/7.5 heteromers but not homomeric Kv7.4, providing differential regulation. Proximity ligation assay, dominant-negative subunit expression, inducible PKCα translocation system, patch-clamp electrophysiology, phosphorylation assay The Journal of biological chemistry High 24297175
2015 KCNE4 co-localizes with Kv7.4 in mesenteric artery smooth muscle cells; co-expression of KCNE4 increases Kv7.4 membrane expression and alters current properties in HEK cells; morpholino-induced KCNE4 knockdown reduces Kv7.4 membrane abundance, depolarizes smooth muscle cells, and augments vasoconstrictor responses. Proximity ligation assay, HEK cell co-expression patch-clamp, morpholino knockdown, isometric tension recording, surface expression quantification The Journal of physiology High 26503181
2015 G-protein βγ subunits (Gβγ) are positive regulators of Kv7.4 channel activity: Gβγ increases open probability of Kv7.4 in excised patches without changing unitary conductance; Kv7.4 and Gβγ co-localize by proximity ligation assay; Gβγ inhibitors abolish basal Kv7 currents and contract whole renal arteries. Excised patch-clamp, whole-cell voltage clamp, proximity ligation assay, pharmacological Gβγ inhibitors (gallein, GRK2i, β-subunit antibody), mSIRK G-protein activator, isometric tension recording Proceedings of the National Academy of Sciences of the United States of America High 25941381
2016 Gβγ and PIP2 act synergistically on Kv7.4: PIP2 depletion abolishes Gβγ-mediated stimulation and Gβγ inhibitors prevent PIP2-induced current enhancement; both act through increased channel open probability, revealing a co-dependent mechanism for Kv7.4 activation. Whole-cell and excised-patch clamp in HEK cells stably expressing Kv7.4, pharmacological PIP2 depletion and Gβγ inhibition Pflugers Archiv : European journal of physiology High 27981364
2016 miR-153 directly targets the 3' UTR of KCNQ4 (validated by luciferase reporter assay); miR-153 is elevated in arteries from spontaneously hypertensive rats where Kv7.4 protein is reduced without mRNA decrease, and introduction of miR-153 into mesenteric arteries reduces Kv7.4 expression, impairs Kv7 function, and causes vascular wall thickening. Luciferase reporter assay, qPCR, western blot, morpholino/miR transfection into isolated arteries, tension recording Cardiovascular research High 27389411
2015 Kv7.4 channels are present in cardiac mitochondria (confirmed by western blot, immunofluorescence co-localization with mitochondrial markers, and immunogold EM); pharmacological Kv7 activation with retigabine depolarizes mitochondrial membrane potential, inhibits mitochondrial Ca2+ uptake, and confers cardioprotection against ischemia-reperfusion injury. Western blot of mitochondrial fractions, immunofluorescence, immunogold EM, Tl+ flux assay, mitochondrial membrane potential measurements, siRNA knockdown, Langendorff heart ischemia-reperfusion Cardiovascular research High 26718475
2012 REST (repressor element-1 silencing transcription factor) binds to four regions in the KCNQ4 5'UTR and first intron; REST expression declines during myotube formation, and REST overexpression reduces Kv7.4 transcript levels; Kv7.4 silencing impairs skeletal muscle differentiation (reduced myogenin, MHC, troponinT-1, Pax3 expression and myotube formation). Chromatin immunoprecipitation (ChIP), RNA interference, qPCR, immunofluorescence differentiation markers in C2C12 cells Molecular biology of the cell High 23242999
2015 Calmodulin (CaM) binds constitutively to two isoforms of KCNQ4 but Ca2+/CaM reduces channel activity only in the long isoform (hKv7.4a) by decreasing open probability and altering activation kinetics; the DFNA2 mutation G321S destabilizes CaM binding, diminishing Ca2+/CaM inhibitory effects. Patch-clamp electrophysiology, CaM mutagenesis, binding assays, multiple biophysical approaches The Journal of biological chemistry High 26515070
2019 Ca2+/CaM undergoes lobe switching upon Ca2+ binding to impose a mutually induced conformational fit on KCNQ4 proximal C-terminal A and B domains; crystal structure confirms CaM binding both A and B domain peptides; C-lobe of apo-CaM interacts with the B domain (~10-20 μM), and increasing Ca2+ shifts interactions to include the N-lobe. X-ray crystallography, isothermal titration calorimetry, microscale thermophoresis, heteronuclear single-quantum coherence NMR, biophysical chemical analysis of synthetic KCNQ4 C-terminal peptides The Journal of biological chemistry High 30808708
2021 The S2-S3 intracellular loop of Kv7.4 is essential for Ca2+/CaM-mediated inhibitory regulation of channel activation; the EF3 hand of CaM controls Ca2+-dependent regulation; mutations C156A, C157A, C158V, R159A, R161A in the S2-S3 loop decrease Ca2+/CaM inhibitory effect; double mutation C156A/R159A completely abolishes Ca2+/CaM-dependent regulation. Patch-clamp electrophysiology, CaM EF-hand mutagenesis, KCNQ4 S2-S3 loop mutagenesis, heterologous expression Frontiers in physiology High 33551832
2021 Dynein motor protein traffics Kv7.4 channels away from the cell membrane via a C-terminal dynein-binding site; inhibiting dynein (ciliobrevin D or p50/dynamitin) increases Kv7.4 currents and membrane abundance; Kv7.4 localizes to caveolae and interacts with caveolin-1, and cholesterol depletion disrupts Kv7.4-caveolin-1-dynein interactions while increasing overall membrane Kv7.4 expression. Patch-clamp electrophysiology, structured illumination microscopy, proximity ligation assay, co-immunoprecipitation, mass spectrometry, morpholino knockdown in arterial segments, cholesterol depletion The Journal of general physiology High 33533890
2013 JAK2 kinase downregulates KCNQ4 channel activity; co-expression of wild-type or constitutively active (V617F)JAK2, but not inactive (K882E)JAK2, significantly decreases KCNQ4-mediated conductance in Xenopus oocytes; JAK2 inhibitor AG490 rescues conductance; brefeldin A experiments indicate JAK2 does not accelerate channel retrieval from the membrane. Xenopus oocyte co-expression, dual-electrode voltage clamp, constitutively active/inactive JAK2 mutants, pharmacological JAK2 inhibition The Journal of membrane biology Medium 23543186
2019 D2 dopamine receptors enhance Kv7.4 currents in VTA dopamine neurons through a Gi/o protein and redox-dependent pathway, contributing to projection-specific auto-inhibition of DA neurons projecting to NAc and basolateral amygdala; this D2-mediated auto-inhibition is blunted in a social defeat depression mouse model. Patch-clamp electrophysiology in VTA neurons, pharmacological Gi/o and redox pathway dissection, mouse social defeat model Frontiers in cellular neuroscience Medium 31920557
2018 Midbrain KCNQ4 expression negatively correlates with alcohol intake in BXD mice; intra-VTA pharmacological activation of Kv7.2/4 channels (novel selective modulator) reduces excessive alcohol drinking in high-drinking rats, establishing a functional role for VTA Kv7.4 in regulating alcohol consumption. Integrative bioinformatics (BXD genetic reference panel), intra-VTA drug microinjection, two-bottle choice alcohol drinking assay in rats Neuropharmacology Medium 29775679
2022 Truncated KCNQ4 variants lacking the C-terminal tetramerization domain (Kv7.4Q71fs, Kv7.4W242X, Kv7.4A349fs) induce cell death (cytotoxicity) in heterologous expression systems independently of dominant-negative inhibition; autophagy inducers ameliorate this cytotoxicity. Heterologous expression of truncated KCNQ4 variants, cell death/viability assays, autophagy inducer treatment Disease models & mechanisms Medium 34622280
2022 Kv7.4 channels are expressed and functional in neuronal mitochondria: Kv7 blocker XE991 reduces and retigabine enhances K+-dependent mitochondrial membrane potential changes in F11 neuronal cells and mouse brain mitochondria; Kv7.4 siRNA knockdown suppresses retigabine-dependent mitochondrial depolarization. Western blot of mitochondrial fractions, immunocytochemistry with Mitotracker co-localization, mitochondrial membrane potential assay, siRNA knockdown, pharmacological Kv7 modulators in intact neurons Biochemical pharmacology Medium 35085542
2022 In vivo CRISPR/Cas9-mediated disruption of the dominant-negative Kcnq4W276S allele in OHCs using dual AAV delivery significantly improves auditory thresholds and results in more hyperpolarized OHC membrane potentials (assessed by thallium live-cell imaging), confirming that mutant KCNQ4 causes OHC depolarization underlying hearing loss. Dual AAV-delivered CRISPR-Cas9 in vivo gene editing, auditory brainstem response, distortion-product otoacoustic emission, thallium live-cell imaging of OHC membrane potential Theranostics High 35265220
2012 KCNQ4 silencing by RNA interference in C2C12 myoblasts reduces expression of muscle differentiation markers and impairs myotube formation; REST transcriptionally represses KCNQ4 by binding to four regions in KCNQ4 regulatory sequences, and REST expression declines during myotube formation to permit KCNQ4 upregulation. RNA interference, ChIP, qPCR, immunofluorescence, C2C12 differentiation assay Molecular biology of the cell High 23242999

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 688 10025409
2000 KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proceedings of the National Academy of Sciences of the United States of America 343 10760300
2006 Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness. The EMBO journal 214 16437162
1999 Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Human molecular genetics 138 10369879
2011 Downregulation of Kv7.4 channel activity in primary and secondary hypertension. Circulation 132 21747056
2005 Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss. The Journal of neuroscience : the official journal of the Society for Neuroscience 105 16207888
2012 Reduced KCNQ4-encoded voltage-dependent potassium channel activity underlies impaired β-adrenoceptor-mediated relaxation of renal arteries in hypertension. Hypertension (Dallas, Tex. : 1979) 98 22353613
2011 KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man. Nature neuroscience 88 22101641
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2000 Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2. Brain research. Molecular brain research 79 11042367
2014 Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity. Arteriosclerosis, thrombosis, and vascular biology 78 24558103
2015 Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection. Cardiovascular research 67 26718475
2023 LncRNA-BC069792 suppresses tumor progression by targeting KCNQ4 in breast cancer. Molecular cancer 65 36859185
2015 Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone. The Journal of physiology 61 26503181
2013 Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. The Journal of biological chemistry 60 24297175
2015 G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity. Proceedings of the National Academy of Sciences of the United States of America 55 25941381
2010 Diclofenac distinguishes among homomeric and heteromeric potassium channels composed of KCNQ4 and KCNQ5 subunits. Molecular pharmacology 50 20876743
1999 Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Human mutation 50 10571947
2013 Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation. PloS one 49 23717403
2006 Functional coassembly of KCNQ4 with KCNE-beta- subunits in Xenopus oocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 47 16914890
2000 Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. American journal of medical genetics 47 10925378
2010 Aminoglycosides inhibit KCNQ4 channels in cochlear outer hair cells via depletion of phosphatidylinositol(4,5)bisphosphate. Molecular pharmacology 46 20935082
2022 In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model. Theranostics 44 35265220
2002 Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family. The Annals of otology, rhinology, and laryngology 44 11915881
2012 Specification of skeletal muscle differentiation by repressor element-1 silencing transcription factor (REST)-regulated Kv7.4 potassium channels. Molecular biology of the cell 43 23242999
2006 A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation. Journal of human genetics 43 16596322
2016 MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension. Cardiovascular research 42 27389411
2011 The voltage-gated potassium channel subfamily KQT member 4 (KCNQ4) displays parallel evolution in echolocating bats. Molecular biology and evolution 42 22319145
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1997 Linkage analysis of progressive hearing loss in five extended families maps the DFNA2 gene to a 1.25-Mb region on chromosome 1p. Genomics 41 9126484
2012 Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers. British journal of pharmacology 40 21951272
2007 A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Human genetics 40 18030493
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2007 Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels. The Journal of biological chemistry 38 17561493
2013 Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models. The Journal of biological chemistry 37 23408425
2008 Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus. Genetics in medicine : official journal of the American College of Medical Genetics 37 18941426
2010 Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. The Journal of biological chemistry 36 20966080
2005 Regulation of the voltage-gated potassium channel KCNQ4 in the auditory pathway. Pflugers Archiv : European journal of physiology 36 15660259
2013 Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. Journal of cellular and molecular medicine 35 23750663
2001 Speech recognition scores related to age and degree of hearing impairment in DFNA2/KCNQ4 and DFNA9/COCH. Archives of otolaryngology--head & neck surgery 34 11556850
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2009 The septate junction protein caspr is required for structural support and retention of KCNQ4 at calyceal synapses of vestibular hair cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 19279247
2005 Regulation of KCNQ4 potassium channel prepulse dependence and current amplitude by SGK1 in Xenopus oocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 32 16301825
2001 Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. Journal of human genetics 32 11450843
2021 Cigarette Smoke Directly Promotes Pulmonary Arterial Remodeling and Kv7.4 Channel Dysfunction. American journal of respiratory and critical care medicine 31 33306938
2005 Phenotype determination guides swift genotyping of a DFNA2/KCNQ4 family with a hot spot mutation (W276S). Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 31 15699719
2013 Distinct roles of molecular chaperones HSP90α and HSP90β in the biogenesis of KCNQ4 channels. PloS one 30 23431407
2006 Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan. Audiology & neuro-otology 28 17033161
2018 Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss. Scientific reports 24 30413759
2014 Targeted high-throughput sequencing identifies pathogenic mutations in KCNQ4 in two large Chinese families with autosomal dominant hearing loss. PloS one 24 25116015
2008 KCNQ4 mutations associated with nonsyndromic progressive sensorineural hearing loss. Current opinion in otolaryngology & head and neck surgery 24 18797286
2004 Modulation of KCNQ4 channel activity by changes in cell volume. Biochimica et biophysica acta 24 14757214
2021 Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss. Experimental & molecular medicine 23 34316018
2010 Effect of salicylate on KCNQ4 of the guinea pig outer hair cell. Journal of neurophysiology 23 20147414
2021 Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss. International journal of molecular sciences 22 33801540
2019 Inner Hair Cell and Neuron Degeneration Contribute to Hearing Loss in a DFNA2-Like Mouse Model. Neuroscience 22 31102762
2019 Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment. Experimental & molecular medicine 22 31434872
2011 Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene. Archives of otolaryngology--head & neck surgery 22 21242547
2010 Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology. Biochimica et biophysica acta 22 20832469
2018 A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators. Human mutation 21 30556268
2003 Voltage-independent KCNQ4 currents induced by (+/-)BMS-204352. Pflugers Archiv : European journal of physiology 21 12851819
2013 Downregulation of KCNQ4 by Janus kinase 2. The Journal of membrane biology 20 23543186
2021 Dynein regulates Kv7.4 channel trafficking from the cell membrane. The Journal of general physiology 17 33533890
2020 Molecular basis and restoration of function deficiencies of Kv7.4 variants associated with inherited hearing loss. Hearing research 17 31995783
2018 Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents. Neuropharmacology 16 29775679
2023 Overlooked KCNQ4 variants augment the risk of hearing loss. Experimental & molecular medicine 15 37009795
2012 Genetics of hearing loss: focus on DFNA2. The application of clinical genetics 15 23776385
2019 A mutually induced conformational fit underlies Ca2+-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K+ channels. The Journal of biological chemistry 14 30808708
2019 Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area. Frontiers in cellular neuroscience 14 31920557
2015 Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels. The Journal of biological chemistry 14 26515070
2011 Identification of novel KCNQ4 openers by a high-throughput fluorescence-based thallium flux assay. Analytical biochemistry 14 21782781
2022 AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss. Human genetics 13 35038006
2022 The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants. Biomedicines 13 36140355
2016 Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity. Pflugers Archiv : European journal of physiology 13 27981364
2022 Proactive functional classification of all possible missense single-nucleotide variants in KCNQ4. Genome research 12 35760561
2021 A KCNQ4 c.546C>G Genetic Variant Associated with Late Onset Non-Syndromic Hearing Loss in a Taiwanese Population. Genes 12 34828318
2019 Novel Mutations in KCNQ4, LHFPL5 and COCH Genes in Iranian Families with Hearing Impairment. Archives of Iranian medicine 12 31126177
2016 Tannic acid activates the Kv7.4 and Kv7.3/7.5 K(+) channels expressed in HEK293 cells and reduces tension in the rat mesenteric arteries. The Journal of pharmacy and pharmacology 12 26969140
2015 A novel KCNQ4 mutation and a private IMMP2L-DOCK4 duplication segregating with nonsyndromic hearing loss in a Brazilian family. Human genome variation 12 27081546
2015 A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss. Biochemical and biophysical research communications 11 26036578
2013 Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL. European journal of human genetics : EJHG 11 23443030
2012 In silico modeling of the pore region of a KCNQ4 missense mutant from a patient with hearing loss. BMC research notes 10 22420747
2011 Audioprofile-directed successful mutation analysis in a DFNA2/KCNQ4 (p.Leu274His) family. The Annals of otology, rhinology, and laryngology 10 21585154
1999 The DFNA2 locus for hearing impairment: two genes regulating K+ ion recycling in the inner ear. British journal of audiology 10 10890142
2022 A humanized murine model, demonstrating dominant progressive hearing loss caused by a novel KCNQ4 mutation (p.G228D) from a large Chinese family. Clinical genetics 9 35599357
2018 Genetic variation in KCNQ4 gene is associated with susceptibility to noise-induced hearing loss in a Chinese population. Environmental toxicology and pharmacology 9 30153627
2017 A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2. BMC medical genetics 9 28340560
2002 Further evidence for a third deafness gene within the DFNA2 locus. American journal of medical genetics 9 11920835
2022 Kv7.4 channels regulate potassium permeability in neuronal mitochondria. Biochemical pharmacology 8 35085542
2021 The S2-S3 Loop of Kv7.4 Channels Is Essential for Calmodulin Regulation of Channel Activation. Frontiers in physiology 8 33551832
2021 A novel KCNQ4 gene variant (c.857A>G; p.Tyr286Cys) in an extended family with non‑syndromic deafness 2A. Molecular medicine reports 8 33846771
2013 Moderate hearing loss associated with a novel KCNQ4 non-truncating mutation located near the N-terminus of the pore helix. Biochemical and biophysical research communications 8 23399560
2012 BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells. Stem cell research 8 23089626
2000 A Dutch family with progressive sensorineural hearing impairment linked to the DFNA2 region. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 8 10784363
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2014 A Japanese family showing high-frequency hearing loss with KCNQ4 and TECTA mutations. Acta oto-laryngologica 7 24655070
2021 Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss. Disease models & mechanisms 6 34622280
2002 Audiologic evidence for further genetic heterogeneity at DFNA2. Acta oto-laryngologica 6 12484650
2023 Valproic Acid Inhibits Progressive Hereditary Hearing Loss in a KCNQ4 Variant Model through HDAC1 Suppression. International journal of molecular sciences 5 36982769