Affinage

Showing KCNQ4 — KV7.4 is a alias.

KCNQ4

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

Length
695 aa
Mass
77.1 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNQ4 (Kv7.4) is a voltage-gated potassium channel that sets the resting membrane potential of cochlear outer hair cells (OHCs) through the slowly activating I(K,n) current at the basolateral membrane, and its loss causes the dominant progressive hearing loss DFNA2: genetic ablation in mice abolishes I(K,n), chronically depolarizes OHCs, and drives their selective degeneration (PMID:10025409, PMID:10760300, PMID:16437162). Pore-region disease mutations act dominant-negatively, predominantly by reducing cell-surface trafficking of the channel without disrupting tetrameric assembly, and this trafficking deficiency can be corrected by HSP90β chaperone activity (PMID:18030493, PMID:23431407, PMID:23750663). Channel gating is governed by phosphoinositide and Ca2+ signaling: KCNQ4 requires PI(4,5)P2 for activity, Gβγ subunits raise open probability by enhancing PIP2 sensitivity, and constitutive calmodulin bound to C-terminal IQ domains mediates Ca2+-dependent inhibition through a mutually induced conformational fit and the S2-S3 loop (PMID:20935082, PMID:25941381, PMID:27981364, PMID:26515070, PMID:30808708, PMID:33551832). C-terminal alternative splicing generates isoforms differing in voltage dependence and calmodulin regulation (PMID:17561493), and additional kinase inputs (PKA, SGK1) shift activation (PMID:15660259, PMID:16301825). Beyond hearing, KCNQ4 is expressed in type I vestibular afferent calyces where it is clustered by Caspr (PMID:23408425, PMID:19279247), in cutaneous mechanoreceptors where it tunes touch sensitivity (PMID:22101641), and in vascular smooth muscle, where it forms predominantly Kv7.4/Kv7.5 heterotetramers regulated by KCNE4, PKC, caveolin-1/dynein-dependent trafficking, and miR-153, mediating β-adrenoceptor- and CGRP-dependent vasodilation that is impaired in hypertension (PMID:21747056, PMID:24297175, PMID:24558103, PMID:26503181, PMID:33533890, PMID:22353613, PMID:27389411). KCNQ4 is also functional in cardiac and neuronal mitochondria, regulating membrane potential and Ca2+ uptake (PMID:26718475, PMID:35085542), and contributes to D2-receptor/Gi/o-mediated auto-inhibition of VTA dopamine neurons (PMID:31920557). In vivo allele-specific CRISPR editing of a dominant-negative DFNA2 allele restores OHC hyperpolarization and auditory function, validating loss-of-function as the disease mechanism (PMID:35265220).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Established why KCNQ4 mutations cause dominant rather than recessive deafness by showing pore mutations act dominant-negatively on co-assembled wild-type channels.

    Evidence Heterologous expression with whole-cell patch-clamp and dominant-negative co-expression assay

    PMID:10025409

    Open questions at the time
    • Did not resolve whether dominant-negative effect reflects loss of conductance or loss of surface trafficking
    • Native OHC consequences not yet shown
  2. 2000 High

    Tied KCNQ4 protein to the functional I(K,n)/g(K,L) currents by localizing it to the basal OHC membrane and type I vestibular hair cell calyces.

    Evidence Immunohistochemistry with specific antibodies and subcellular localization

    PMID:10760300

    Open questions at the time
    • Localization correlative rather than functional
    • Did not test channel necessity in vivo
  3. 2006 High

    Demonstrated in vivo that KCNQ4 maintains OHC membrane potential and survival, defining the cellular basis of progressive hearing loss.

    Evidence Knockout and dominant-negative knock-in mice with auditory physiology, OHC patch-clamp, and histology

    PMID:16437162

    Open questions at the time
    • Mechanism linking chronic depolarization to selective degeneration not defined
    • No therapeutic intervention tested
  4. 2007 High

    Refined the dominant-negative mechanism by showing pore mutations primarily reduce surface trafficking, and that C-terminal splicing diversifies channel gating and calmodulin regulation.

    Evidence Oocyte and heterologous electrophysiology, surface immunolabeling of HA-tagged channels, and splice-variant characterization

    PMID:17561493 PMID:18030493

    Open questions at the time
    • Chaperone machinery controlling trafficking not yet identified
    • Physiological isoform distribution across tissues unresolved
  5. 2013 High

    Identified the chaperone network controlling KCNQ4 biogenesis and showed HSP90β can rescue trafficking-deficient disease mutants, defining a druggable proteostasis axis.

    Evidence Proteomics, reciprocal co-IP, and overexpression/siRNA with surface-expression rescue of DFNA2 mutants

    PMID:23431407 PMID:23750663

    Open questions at the time
    • HSP90β rescues surface expression but not conductance of pore mutants
    • Endogenous regulation of HSP90α vs HSP90β balance unclear
  6. 2011 High

    Extended KCNQ4 function beyond the cochlea to cutaneous mechanoreceptors and to vascular smooth muscle, where its downregulation impairs vasorelaxation in hypertension.

    Evidence Single-unit recordings in mouse models plus human psychophysics; qPCR/Western/myography in hypertensive rat and angiotensin II models

    PMID:21747056 PMID:22101641

    Open questions at the time
    • Touch-sensitivity mechanism at the molecular level not detailed
    • Cause of vascular downregulation in hypertension not yet defined
  7. 2013 High

    Defined the predominant vascular channel form as Kv7.4/Kv7.5 heterotetramers with composition-dependent PKC regulation, and placed KCNQ4/KCNQ5 postsynaptically in vestibular calyces.

    Evidence Proximity ligation, dominant-negative electrophysiology, siRNA, myography, and immunolocalization in genetic models

    PMID:23408425 PMID:24297175 PMID:24558103

    Open questions at the time
    • Exact subunit stoichiometry not resolved at this stage
    • Tissue-specific regulatory differences mechanistically incomplete
  8. 2010 High

    Revealed PI(4,5)P2 as an obligatory cofactor for KCNQ4 activity, mechanistically explaining aminoglycoside and salicylate ototoxicity.

    Evidence OHC and recombinant patch-clamp with PI(4,5)P2 imaging and pharmacological dissection

    PMID:20147414 PMID:20935082

    Open questions at the time
    • Structural basis of PIP2 binding not defined
    • Salicylate binding site on the channel not mapped
  9. 2015 High

    Identified Gβγ and KCNE4 as positive regulators of Kv7.4 in vasculature, with Gβγ acting by potentiating PIP2 sensitivity.

    Evidence Excised-patch single-channel recordings, proximity ligation, HEK co-expression, morpholino knockdown, and tension recording

    PMID:25941381 PMID:26503181 PMID:27981364

    Open questions at the time
    • Structural mechanism of Gβγ-PIP2 synergy not established
    • Gβγ/PIP2 coupling shown pharmacologically without structural validation
  10. 2019 High

    Resolved the structural and molecular basis of Ca2+/calmodulin regulation, defining a mutually induced fit at the proximal C-terminus and the S2-S3 loop as the inhibitory element.

    Evidence X-ray crystallography, ITC, NMR, thermophoresis (2019); systematic CaM and S2-S3 loop mutagenesis with patch-clamp (2021); isoform-specific CaM dissection (2015)

    PMID:26515070 PMID:30808708 PMID:33551832

    Open questions at the time
    • Full-length channel structure with CaM not solved
    • How CaM regulation integrates with PIP2 occupancy unresolved
  11. 2021 Medium

    Defined trafficking control of vascular Kv7.4 by caveolin-1/dynein and post-transcriptional suppression by miR-153, linking channel surface abundance to hypertension.

    Evidence Co-IP, proximity ligation, super-resolution microscopy, mass spectrometry, dynein-site mutagenesis; luciferase 3'UTR reporter and miR-153 overexpression in arteries

    PMID:27389411 PMID:33533890

    Open questions at the time
    • In vivo contribution of dynein trafficking to blood pressure not tested
    • miR-153 luciferase/overexpression evidence from a single lab
  12. 2022 High

    Provided in vivo proof that restoring KCNQ4 function corrects the disease, by allele-specific CRISPR disruption of a dominant-negative allele that recovered OHC hyperpolarization and hearing.

    Evidence In vivo dual-AAV CRISPR-Cas9 editing with ABR/DPOAE and thallium live-cell imaging; complementary VPA/HSP90β and autophagy-inducer rescue studies

    PMID:34622280 PMID:35265220 PMID:36982769

    Open questions at the time
    • Durability and off-target effects of editing not fully characterized
    • Cytotoxicity of truncated variants and autophagy rescue shown only in heterologous cells

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KCNQ4 mitochondrial channels are imported and gated, and how its diverse extra-cochlear roles (mitochondria, dopaminergic auto-inhibition, mechanotransduction) are integrated, remain unresolved.
  • No import/topology mechanism for mitochondrial Kv7.4
  • Redox-dependent D2/Gi-o coupling mechanism undefined
  • No structure of full-length channel in any tissue context

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
CALM1CAV1CNTNAP1HSP90AB1KCNE4KCNQ5
Complex memberships
Kv7.4/Kv7.5 heterotetramer

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 KCNQ4 encodes a voltage-gated potassium channel expressed in cochlear outer hair cells (OHCs); a pore-region mutation (G285S equivalent) abolishes K+ currents of wild-type KCNQ4 and exerts a strong dominant-negative effect on co-expressed wild-type channels, establishing loss-of-function via dominant-negative mechanism as the basis of DFNA2 hearing loss intrinsic to OHCs. Heterologous expression with whole-cell patch-clamp electrophysiology; dominant-negative co-expression assay Cell High 10025409
2000 KCNQ4 protein is localized to the basal membrane of cochlear outer hair cells and is restricted to type I vestibular hair cells and their afferent calyx-like nerve endings; immunohistochemical evidence supports KCNQ4 as the molecular basis for the I(K,n) and g(K,L) currents open at resting potentials in OHCs and type I hair cells. Immunohistochemistry with specific antibodies; subcellular fractionation/localization Proceedings of the National Academy of Sciences of the United States of America High 10760300
2006 Genetic disruption of KCNQ4 in mice abolishes the I(K,n) current in OHCs, causing chronic depolarization that leads to selective progressive OHC degeneration and hearing loss; inner hair cells remain largely intact and show near-normal presynaptic function, demonstrating KCNQ4's essential role in maintaining OHC membrane potential and survival. Knockout and dominant-negative knock-in mouse models; in vivo auditory function (ABR/DPOAE); patch-clamp of isolated OHCs; histological analysis The EMBO journal High 16437162
2007 Alternative splicing of KCNQ4 at the C-terminal membrane-proximal region (exons 9–11) produces four functional isoforms (v1–v4) with profoundly different voltage-dependent activation (v4 shifted ~20 mV leftward vs. v1) and expression levels; the isoforms are differentially regulated by calmodulin due to variations in their calmodulin-binding domains, and can form heterotetramers. Patch-clamp electrophysiology of splice variants expressed in heterologous cells; dominant-negative co-expression; calmodulin modulation assays The Journal of biological chemistry High 17561493
2007 A KCNQ4 pore-region mutation (p.G296S) causes dominant deafness primarily by severely reducing cell-surface expression of the channel (trafficking deficiency), rather than solely abolishing conductance; the trafficking-deficient mutant exerts dominant-negative effects by reducing wild-type KCNQ4 surface expression. Xenopus oocyte electrophysiology; non-permeabilized cell surface immunolabeling (HA-tagged KCNQ4); co-expression dominant-negative assay in oocytes Human genetics High 18030493
2010 Aminoglycoside antibiotics inhibit KCNQ4-mediated I(K,n) in OHCs by depleting phosphatidylinositol(4,5)bisphosphate [PI(4,5)P2]; PI(4,5)P2 is required for KCNQ4 activity, and AGs sequester PI(4,5)P2, causing OHC depolarization. Potency of inhibition correlates with known ototoxic potential of individual aminoglycosides. Whole-cell patch-clamp of rat OHCs and recombinant KCNQ channels; fluorescence imaging of cellular PI(4,5)P2; pharmacological rescue with KCNQ openers Molecular pharmacology High 20935082
2011 KCNQ4 is expressed in peripheral nerve endings of cutaneous rapidly adapting hair follicle and Meissner corpuscle mechanoreceptors; loss of KCNQ4 elevates mechanosensitivity and alters frequency response of rapidly adapting but not slowly adapting mechanoreceptors, establishing KCNQ4 as a molecular regulator of touch sensitivity. Single-unit electrophysiological recordings from Kcnq4−/− mice and DFNA2 knock-in mice; immunohistochemistry; vibrotactile testing in human DFNA2 subjects Nature neuroscience High 22101641
2011 KCNQ4 (Kv7.4) channel expression and function are specifically downregulated (~3.7-fold mRNA, ~50% protein) in aortas and mesenteric arteries of spontaneously hypertensive rats compared to normotensive controls, impairing Kv7-dependent vascular relaxation; similar attenuation found in angiotensin II-infused hypertensive mice. Quantitative PCR; Western blot; isometric tension recording; patch-clamp of isolated myocytes; pharmacological Kv7 activators/blockers Circulation High 21747056
2012 Kv7.4 (KCNQ4) channels are physically present and functional in cardiac mitochondria; Kv7 activators (retigabine, flupirtine) increase Tl+ influx, depolarize mitochondrial membrane potential, and inhibit calcium uptake in isolated cardiac mitochondria in a XE991-sensitive manner; Kv7.4 silencing blunts these effects, and Kv7.4 activation exerts cardioprotective effects against ischemia-reperfusion injury. Western blot of mitochondrial fractions; immunofluorescence co-localization with mitochondrial markers; immunogold electron microscopy; Tl+ influx assay; mitochondrial membrane potential measurement; RNA interference; Langendorff heart preparation Cardiovascular research High 26718475
2013 Kv7.4 and Kv7.5 subunits form predominantly heteromeric channels (Kv7.4/Kv7.5 heteromers) in vascular smooth muscle cells, demonstrated by proximity ligation assay; both subunits are regulated by PKC-dependent phosphorylation, but Kv7.4 homomers are not suppressed by PKCα or arginine vasopressin while Kv7.5 and Kv7.4/Kv7.5 heteromers are, revealing differential PKC regulation dependent on subunit composition. Proximity ligation assay; dominant-negative patch-clamp; inducible PKCα translocation system; phosphorylation assay; whole-cell electrophysiology The Journal of biological chemistry High 24297175
2013 In vestibular organs, KCNQ4 and KCNQ5 reside postsynaptically in calyx-forming afferent neurons (not in the hair cells themselves); loss of KCNQ4 and/or KCNQ5 causes mild vestibulo-ocular reflex deficits, with KCNQ4 having greater impact due to its expression in central zones of maculae/cristae innervated by phasic neurons. Immunolocalization in Kcnq4−/− and dominant-negative knock-in mice; whole-cell recordings of vestibular hair cells; vestibulo-ocular reflex testing The Journal of biological chemistry High 23408425
2013 In cerebral arteries, Kv7.4 and Kv7.5 exist predominantly as functional heterotetramers (Kv7.4/Kv7.5); Kv7.4 (but not Kv7.5) is required for CGRP-induced vasodilation, while both subunits contribute to myogenic constriction. Unlike systemic arteries, Kv7 function and Kv7.4 abundance in cerebral arteries are not altered in hypertensive animals. Proximity ligation assay; siRNA knockdown; isometric and isobaric myography; pharmacological Kv7 blockers Arteriosclerosis, thrombosis, and vascular biology High 24558103
2013 HSP70 and HSP90 are KCNQ4-associated chaperones (identified by proteomics and confirmed by reciprocal co-IP); HSP90β increases KCNQ4 cell-surface expression while HSP90α has opposite effects; HSP40, HSP70, and HOP facilitate KCNQ4 biogenesis, and CHIP (E3 ubiquitin ligase) promotes KCNQ4 degradation. HSP90β overexpression improves surface expression of trafficking-deficient DFNA2 mutants L274H and W276S. Proteomics; reciprocal co-immunoprecipitation; Western blot; immunofluorescence; siRNA/overexpression PloS one High 23431407
2013 Decreased KCNQ4 surface expression is a major mechanism underlying dominant-negative DFNA2 mutations (L274H, W276S, L281S, G285C, G285S, G296S, G321S); these mutations reduce plasma membrane trafficking without affecting tetrameric assembly; HSP90β overexpression restores surface expression of selected mutants though not their conductance. Immunofluorescence; Western blot; patch-clamp electrophysiology; co-IP for tetramer assembly Journal of cellular and molecular medicine High 23750663
2015 KCNE4 ancillary subunit co-localizes with Kv7.4 in mesenteric artery myocytes; KCNE4 co-expression in HEK cells increases Kv7.4 membrane expression and alters current properties; morpholino knockdown of KCNE4 in arteries reduces Kv7.4 membrane abundance, depolarizes smooth muscle cells, and augments vasoconstrictor sensitivity, demonstrating KCNE4 as a key regulator of Kv7.4 function and membrane localization in vascular smooth muscle. Proximity ligation assay; HEK cell co-expression electrophysiology; morpholino knockdown; quantitative PCR; isometric tension recording The Journal of physiology High 26503181
2015 Gβγ subunits of G proteins are positive regulators of Kv7.4 channel activity; Gβγ increases Kv7.4 open probability in excised patches without changing unitary conductance; Gβγ and Kv7.4 colocalize (proximity ligation assay); Gβγ inhibition (gallein) contracts renal arteries and impairs isoproterenol relaxation, placing Gβγ as required for basal Kv7.4 activity in vascular smooth muscle. Whole-cell and excised patch-clamp; proximity ligation assay; pharmacological Gβγ inhibitors; isometric tension recording Proceedings of the National Academy of Sciences of the United States of America High 25941381
2016 Gβγ increases Kv7.4 activity by enhancing its sensitivity to PIP2; PIP2 depletion abolishes Gβγ-mediated stimulation, and Gβγ inhibitors abolish PIP2-induced current enhancement, revealing synergistic interplay between Gβγ and PIP2 as the fundamental mechanism governing Kv7.4 channel open probability. Whole-cell patch-clamp in HEK cells stably expressing Kv7.4; pharmacological PIP2 depletion and Gβγ inhibition Pflugers Archiv : European journal of physiology Medium 27981364
2016 miR-153 directly targets the 3' UTR of KCNQ4 and reduces Kv7.4 protein expression post-transcriptionally; miR-153 is elevated in arteries of spontaneously hypertensive rats where Kv7.4 protein is decreased without reduction in KCNQ4 mRNA; miR-153 introduction into mesenteric arteries increases vascular wall thickening and reduces Kv7.4 abundance/function. Luciferase reporter assay; quantitative PCR; Western blot; isometric tension recording; miR-153 overexpression in arteries Cardiovascular research Medium 27389411
2012 REST (repressor element-1 silencing transcription factor) transcriptionally represses KCNQ4 expression by binding to regulatory regions in the 5'UTR and first intron of the KCNQ4 gene; REST binding decreases during myotube formation and Kv7.4 silencing impairs skeletal muscle differentiation (reduced myogenin, MHC, troponinT-1, Pax3 and myotube formation). Chromatin immunoprecipitation (ChIP); RNA interference; REST overexpression; differentiation marker Western blot/immunofluorescence Molecular biology of the cell High 23242999
2005 KCNQ4 channel activity is regulated by PKA phosphorylation: 8-bromo-cAMP or PKA catalytic subunit shifts activation V(1/2) by approximately −10 to −20 mV in CHO cells; co-expression with prestin (OHC motor protein) shifts activation by an additional −15 mV; elevated intracellular Ca2+ causes rapid current run-down via calmodulin/calcineurin, which is prevented by PKA. Whole-cell patch-clamp in CHO cells; pharmacological PKA activation; co-expression with prestin; calcium chelation experiments; calmodulin/calcineurin inhibitors Pflugers Archiv : European journal of physiology Medium 15660259
2005 SGK1 (serum- and glucocorticoid-inducible kinase 1) increases KCNQ4 current amplitude by ~67% and hyperpolarizes resting potential in Xenopus oocytes; inactive SGK1 (K127N) has no effect; mutation of putative SGK1 phosphorylation sites in KCNQ4 reduces sensitivity, indicating direct SGK1-mediated regulation of KCNQ4. Xenopus oocyte expression; two-electrode voltage clamp; kinase-dead mutant co-expression; KCNQ4 phosphorylation site mutagenesis Cellular physiology and biochemistry Medium 16301825
2006 All five KCNE β-subunit isoforms (KCNE1–5) are expressed in OHCs and modulate KCNQ4 voltage dependence, protein stability, and ion selectivity when co-expressed in Xenopus oocytes; the JLNS-associated mutation KCNE1(D76N) impairs KCNQ4 function whereas the Romano-Ward mutation KCNE1(S74L) does not. RT-PCR from OHCs; Xenopus oocyte co-expression electrophysiology; two-electrode voltage clamp Cellular physiology and biochemistry Medium 16914890
2009 Caspr (contactin-associated protein) is required for retention/clustering of KCNQ4 at the postsynaptic membranes of calyceal synapses on type I vestibular hair cells; in Caspr knockout mice, the calyceal membrane separation is irregular and KCNQ4 fails to cluster, appearing diffuse along the calyceal membrane, revealing Caspr as a structural organizer of KCNQ4 at these synapses. Immunolabeling; freeze-fracture electron microscopy; Caspr knockout mouse analysis; ultrastructural analysis The Journal of neuroscience High 19279247
2015 KCNQ4 channels are expressed and functional in calmodulin-binding-dependent manner: calmodulin (CaM) binds constitutively to IQ domains in the C-terminus of both Kv7.4a and Kv7.4b isoforms, but only the long isoform Kv7.4a is functionally regulated by Ca2+/CaM (decreasing open probability and altering activation kinetics); the DFNA2 mutation G321S destabilizes CaM binding. Patch-clamp electrophysiology; binding assays; mutagenesis of CaM-binding domain The Journal of biological chemistry High 26515070
2019 Ca2+/calmodulin undergoes a dramatic mutually induced conformational fit with the proximal C-terminus of KCNQ4: in the absence of CaM, the A and B domain peptides are disordered; Ca2+/CaM imposes helical structure on both domains; the CaM C-lobe interacts with the B domain without Ca2+, and increasing Ca2+ causes lobe switching to involve both CaM lobes. Crystal structure confirmed CaM/KCNQ4 AB domain complex formation. X-ray crystallography; isothermal titration calorimetry; microscale thermophoresis; HSQC NMR spectroscopy The Journal of biological chemistry High 30808708
2021 The S2-S3 loop of Kv7.4 is essential for Ca2+/CaM-mediated inhibition of channel activation; the EF3 hand of CaM specifically controls calcium-dependent regulation; mutations in the S2-S3 loop (C156A, C157A, C158V, R159A, R161A) dramatically facilitate activation and abolish Ca2+/CaM inhibitory regulation; the double mutant C156A/R159A decreases Ca2+/CaM binding and completely abolishes this regulation. Whole-cell patch-clamp electrophysiology; CaM mutant co-expression; site-directed mutagenesis of S2-S3 loop Frontiers in physiology High 33551832
2013 JAK2 (Janus kinase 2) downregulates KCNQ4 channel activity in Xenopus oocytes; constitutively active (V617F)JAK2 reduces conductance while kinase-inactive (K882E)JAK2 does not; JAK2 inhibitor AG490 reverses this effect; the mechanism does not involve accelerated channel retrieval from the membrane (brefeldin A experiments), suggesting JAK2 affects channel gating or trafficking differently. Xenopus oocyte expression; two-electrode voltage clamp; constitutively active and kinase-dead JAK2 mutants; brefeldin A treatment The Journal of membrane biology Medium 23543186
2004 KCNQ4 channels expressed in HEK293 cells are modulated by cell volume: channel activity increases with cell swelling and decreases with shrinkage; KCNQ4 contributes significantly to regulatory volume decrease; under isoosmotic conditions, activity is modulated by PKA, PKC, G protein activation, and reduced intracellular Ca2+, but none of these pathways accounts for volume-induced activation. Whole-cell patch-clamp in HEK293 cells; osmotic challenge; pharmacological kinase/G protein modulators Biochimica et biophysica acta Medium 14757214
2021 Dynein motor protein traffics Kv7.4 channels away from the cell membrane; dynein inhibition (ciliobrevin D) or disruption of dynein function (p50/dynamitin) increases Kv7.4 currents and membrane abundance; a dynein-binding site in the Kv7.4 C-terminus is required; Kv7.4 localizes to cholesterol-rich caveolae via interaction with caveolin-1 (confirmed by proximity ligation, co-IP, and structured illumination microscopy), and cholesterol depletion reduces Kv7.4-caveolin-1-dynein interaction while increasing overall Kv7.4 membrane expression. Patch-clamp; proximity ligation assay; co-immunoprecipitation; structured illumination microscopy; mass spectrometry; cholesterol depletion; morpholino knockdown; site-directed mutagenesis of dynein-binding site The Journal of general physiology High 33533890
2012 KCNQ4 (Kv7.4) channels are required for β-adrenoceptor-mediated vasodilation in renal arteries; siRNA knockdown of KCNQ4 (~60% protein reduction) attenuates isoproterenol-induced relaxation; Kv7.4 protein is similarly reduced (~60%) in spontaneously hypertensive rat renal arteries, explaining impaired β-adrenoceptor-mediated dilation in hypertension. siRNA knockdown; isometric tension recording; patch-clamp of smooth muscle cells; quantitative PCR; immunohistochemistry Hypertension (Dallas, Tex. : 1979) High 22353613
2021 Kv7.4 channels are expressed in cardiac mitochondria of neurons (F11 cells and mouse brain); Kv7 activator retigabine decreases neuronal mitochondrial membrane potential, and this effect is abolished by Kv7.4 silencing; Kv7.4 regulates mitochondrial Ca2+ uptake and ROS production in neuronal mitochondria. Western blot of mitochondrial fractions; immunocytochemistry with Mitotracker; Kv7.4 siRNA silencing; mitochondrial membrane potential and Ca2+ measurements Biochemical pharmacology Medium 35085542
2012 KCNQ4 pore-region mutations causing DFNA2 (in the pore) abolish channel function completely and are unresponsive to KCNQ channel openers; however, a C-terminal proximal mutation can be rescued by combined retigabine + zinc pyrithione; in dominant-negative co-expression conditions, channel openers restore currents to near wild-type by strongly activating the small fraction of homomeric wild-type channels. Whole-cell patch-clamp in CHO cells; co-expression of wild-type and mutant KCNQ4; pharmacological rescue experiments British journal of pharmacology High 21951272
2019 Kv7.4 channels contribute to dopamine (DA)-mediated auto-inhibition of VTA dopaminergic neurons projecting to NAc and BLA; D2 receptors enhance Kv7.4 currents through Gi/o protein and a redox-dependent pathway; this D2-mediated auto-inhibition is blunted in a social defeat mouse model of depression. Patch-clamp electrophysiology of VTA DA neurons; pharmacological Gi/o and D2 receptor manipulation; redox pathway blockers; social defeat behavioral model Frontiers in cellular neuroscience Medium 31920557
2021 Truncated Kv7.4 variants (Kv7.4Q71fs, Kv7.4W242X, Kv7.4A349fs) associated with DFNA2 induce cell death (cytotoxicity) when expressed in heterologous systems, beyond haploinsufficiency; autophagy inducers ameliorate this cytotoxicity, providing a novel pathological mechanism for dominant hearing loss. Heterologous cell expression; cell viability assays; autophagy inducer treatment Disease models & mechanisms Medium 34622280
2022 In vivo CRISPR-Cas9 gene editing targeting the dominant-negative Kcnq4W276S allele in OHCs (via dual-AAV delivery) significantly improves auditory thresholds (ABR and DPOAE) and restores OHC hyperpolarization as measured by thallium ion live-cell imaging, confirming that allele-specific disruption restores KCNQ4 channel activity. CRISPR-Cas9 in vivo gene editing; dual-AAV delivery; ABR and DPOAE auditory testing; thallium ion live-cell imaging of OHC membrane potential Theranostics High 35265220
2020 Heteromeric Kv7.4/Kv7.5 channels with a 2:2 alternating stoichiometry reproduce the specific biophysical, regulatory, and pharmacological characteristics of native smooth muscle M-currents; concatenated dimer/tetramer constructs show that alternating Kv7.4-Kv7.5 arrangement uniquely reproduces native current properties, constraining the subunit assembly configuration. Concatenated dimer/tetramer constructs expressed in smooth muscle cell line; whole-cell patch-clamp electrophysiology; pharmacological characterization Frontiers in physiology Medium 32903335
2021 Kv7.4 channel expression and activity are diminished in pulmonary arteries of cigarette smoke-exposed mice, smokers, and COPD patients; cigarette smoke extract directly reduces Kv7.4 expression and impairs vasoconstriction/vasodilation responses in human pulmonary artery cells; antioxidants reverse these effects. Patch-clamp; wire myography; Western blot; traction force microscopy; in vivo smoke-exposure model; antioxidant treatment American journal of respiratory and critical care medicine Medium 33306938
2021 VPA treatment increases KCNQ4 binding with HSP90β by inhibiting HDAC1 activation in cochlear cells in vitro; in the KCNQ4 p.W276S mouse model, systemic VPA attenuates hearing loss and protects OHCs from cell death, linking HDAC1-dependent HSP90β regulation to KCNQ4 protein stability. Co-immunoprecipitation; cell viability assays; ABR/DPOAE in vivo; cochlear histology; chromatin acetylation assay International journal of molecular sciences Medium 36982769
2010 Salicylate at clinical/physiological concentrations causes concentration-dependent, reversible reduction in KCNQ4-mediated I(K,n) in OHCs by direct blocking action on KCNQ4 channels; nonstationary fluctuation analysis shows salicylate reduces single-channel current amplitude and channel number; intracellular Ca2+ elevation also contributes to I(K,n) reduction. Whole-cell patch-clamp of guinea pig OHCs; patch-clamp of KCNQ4-expressing CHO cells; nonstationary fluctuation analysis; pharmacological dissection Journal of neurophysiology Medium 20147414

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 690 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 344 10760300
2006 Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness. The EMBO journal 217 16437162
1999 Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Human molecular genetics 139 10369879
2011 Downregulation of Kv7.4 channel activity in primary and secondary hypertension. Circulation 134 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) 99 22353613
2011 KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man. Nature neuroscience 89 22101641
2006 KCNQ4: a gene for age-related hearing impairment? Human mutation 85 16917933
2014 Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity. Arteriosclerosis, thrombosis, and vascular biology 81 24558103
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
2023 LncRNA-BC069792 suppresses tumor progression by targeting KCNQ4 in breast cancer. Molecular cancer 68 36859185
2015 Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection. Cardiovascular research 67 26718475
2015 Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone. The Journal of physiology 62 26503181
2013 Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. The Journal of biological chemistry 62 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 57 25941381
2010 Diclofenac distinguishes among homomeric and heteromeric potassium channels composed of KCNQ4 and KCNQ5 subunits. Molecular pharmacology 52 20876743
2013 Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation. PloS one 50 23717403
1999 Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Human mutation 50 10571947
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 48 16914890
2010 Aminoglycosides inhibit KCNQ4 channels in cochlear outer hair cells via depletion of phosphatidylinositol(4,5)bisphosphate. Molecular pharmacology 47 20935082
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
2022 In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model. Theranostics 45 35265220
2016 MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension. Cardiovascular research 45 27389411
2006 A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation. Journal of human genetics 44 16596322
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
2011 The voltage-gated potassium channel subfamily KQT member 4 (KCNQ4) displays parallel evolution in echolocating bats. Molecular biology and evolution 42 22319145
2002 A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. Human mutation 42 12112653
2012 Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers. British journal of pharmacology 41 21951272
2007 A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Human genetics 40 18030493
2013 Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models. The Journal of biological chemistry 38 23408425
2011 Parallel evolution of KCNQ4 in echolocating bats. PloS one 38 22046315
2007 Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels. The Journal of biological chemistry 38 17561493
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
2005 Regulation of the voltage-gated potassium channel KCNQ4 in the auditory pathway. Pflugers Archiv : European journal of physiology 37 15660259
2013 Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. Journal of cellular and molecular medicine 35 23750663
2021 Cigarette Smoke Directly Promotes Pulmonary Arterial Remodeling and Kv7.4 Channel Dysfunction. American journal of respiratory and critical care medicine 34 33306938
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
2007 Developmental expression of Kcnq4 in vestibular neurons and neurosensory epithelia. Brain research 33 17292869
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
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
2021 Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss. International journal of molecular sciences 24 33801540
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
2019 Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment. Experimental & molecular medicine 23 31434872
2010 Effect of salicylate on KCNQ4 of the guinea pig outer hair cell. Journal of neurophysiology 23 20147414
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 18 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
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
2016 Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity. Pflugers Archiv : European journal of physiology 14 27981364
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 Proactive functional classification of all possible missense single-nucleotide variants in KCNQ4. Genome research 13 35760561
2022 The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants. Biomedicines 13 36140355
2021 A KCNQ4 c.546C>G Genetic Variant Associated with Late Onset Non-Syndromic Hearing Loss in a Taiwanese Population. Genes 13 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
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
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
2021 miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model. The journal of physiological sciences : JPS 8 34479475
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
2021 Alteration of Mesopontine Cholinergic Function by the Lack of KCNQ4 Subunit. Frontiers in cellular neuroscience 7 34381336
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
2023 Valproic Acid Inhibits Progressive Hereditary Hearing Loss in a KCNQ4 Variant Model through HDAC1 Suppression. International journal of molecular sciences 5 36982769
2020 Heteromeric Channels Formed From Alternating Kv7.4 and Kv7.5 α-Subunits Display Biophysical, Regulatory, and Pharmacological Characteristics of Smooth Muscle M-Currents. Frontiers in physiology 5 32903335
2021 Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms. Free radical biology & medicine 4 34863875
2009 Functional study of the effect of phosphatase inhibitors on KCNQ4 channels expressed in Xenopus oocytes. Acta pharmacologica Sinica 4 19701239
2006 Studies of the effect of ionomycin on the KCNQ4 channel expressed in Xenopus oocytes. Biochemical and biophysical research communications 4 16876114
2023 KCNQ4 potassium channel subunit deletion leads to exaggerated acoustic startle reflex in mice. Neuroreport 3 36789839
2023 Natural History of KCNQ4 p.G285S Related Hearing Loss, Construction of iPSC and Mouse Model. The Laryngoscope 3 37962101
2020 The agonistic action of URO-K10 on Kv7.4 and 7.5 channels is attenuated by co-expression of KCNE4 ancillary subunit. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 3 33093272
2020 Molecular simulation of the Kv7.4[ΔS269] mutant channel reveals that ion conduction in the cavity is perturbed due to hydrophobic gating. Biochemistry and biophysics reports 3 33367117

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