{"gene":"KCNQ4","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"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.","method":"Heterologous expression with whole-cell patch-clamp electrophysiology; dominant-negative co-expression assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro electrophysiology with mutagenesis, foundational paper replicated across multiple subsequent studies","pmids":["10025409"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Immunohistochemistry with specific antibodies; subcellular fractionation/localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with specific antibodies, replicated in multiple subsequent studies, tied to functional current identity","pmids":["10760300"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Knockout and dominant-negative knock-in mouse models; in vivo auditory function (ABR/DPOAE); patch-clamp of isolated OHCs; histological analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic loss-of-function with multiple orthogonal phenotypic readouts (electrophysiology, histology, auditory function), confirmed in two alleles","pmids":["16437162"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Patch-clamp electrophysiology of splice variants expressed in heterologous cells; dominant-negative co-expression; calmodulin modulation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with multiple isoforms and mutagenesis-based dominant-negative approach, single lab with multiple orthogonal methods","pmids":["17561493"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Xenopus oocyte electrophysiology; non-permeabilized cell surface immunolabeling (HA-tagged KCNQ4); co-expression dominant-negative assay in oocytes","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — electrophysiology plus direct cell-surface labeling, two orthogonal methods, single lab","pmids":["18030493"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Whole-cell patch-clamp of rat OHCs and recombinant KCNQ channels; fluorescence imaging of cellular PI(4,5)P2; pharmacological rescue with KCNQ openers","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — patch-clamp with fluorescence imaging of PI(4,5)P2, multiple aminoglycosides tested, mechanistic link confirmed by PI(4,5)P2 availability manipulation","pmids":["20935082"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Single-unit electrophysiological recordings from Kcnq4−/− mice and DFNA2 knock-in mice; immunohistochemistry; vibrotactile testing in human DFNA2 subjects","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo single-unit recordings in multiple genetic models plus human psychophysics, replicated across mouse and human","pmids":["22101641"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Quantitative PCR; Western blot; isometric tension recording; patch-clamp of isolated myocytes; pharmacological Kv7 activators/blockers","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (PCR, WB, electrophysiology, myography), replicated in two independent hypertension models","pmids":["21747056"],"is_preprint":false},{"year":2012,"finding":"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.","method":"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","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (immunogold EM, WB, functional flux assays, RNAi, whole-heart preparation), single lab","pmids":["26718475"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Proximity ligation assay; dominant-negative patch-clamp; inducible PKCα translocation system; phosphorylation assay; whole-cell electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proximity ligation assay for heteromer detection plus dominant-negative electrophysiology and phosphorylation assays, multiple orthogonal approaches, single lab","pmids":["24297175"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Immunolocalization in Kcnq4−/− and dominant-negative knock-in mice; whole-cell recordings of vestibular hair cells; vestibulo-ocular reflex testing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic models with direct electrophysiology and functional vestibular testing, multiple genotypes compared","pmids":["23408425"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Proximity ligation assay; siRNA knockdown; isometric and isobaric myography; pharmacological Kv7 blockers","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proximity ligation plus siRNA knockdown with functional myography, multiple orthogonal approaches","pmids":["24558103"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Proteomics; reciprocal co-immunoprecipitation; Western blot; immunofluorescence; siRNA/overexpression","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP confirmed by proteomics, functional rescue with chaperone manipulation, single lab with multiple orthogonal methods","pmids":["23431407"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Immunofluorescence; Western blot; patch-clamp electrophysiology; co-IP for tetramer assembly","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — electrophysiology plus surface immunolabeling across multiple mutants, single lab with multiple orthogonal methods","pmids":["23750663"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Proximity ligation assay; HEK cell co-expression electrophysiology; morpholino knockdown; quantitative PCR; isometric tension recording","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proximity ligation, electrophysiology, morpholino KD with functional myography, multiple orthogonal methods, single lab","pmids":["26503181"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Whole-cell and excised patch-clamp; proximity ligation assay; pharmacological Gβγ inhibitors; isometric tension recording","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — excised patch single-channel recordings plus proximity ligation and functional vascular assays, multiple orthogonal methods","pmids":["25941381"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Whole-cell patch-clamp in HEK cells stably expressing Kv7.4; pharmacological PIP2 depletion and Gβγ inhibition","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological approach in single expression system, single lab, no structural validation","pmids":["27981364"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Luciferase reporter assay; quantitative PCR; Western blot; isometric tension recording; miR-153 overexpression in arteries","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay confirms direct 3'UTR targeting, functional vascular experiments, single lab","pmids":["27389411"],"is_preprint":false},{"year":2012,"finding":"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).","method":"Chromatin immunoprecipitation (ChIP); RNA interference; REST overexpression; differentiation marker Western blot/immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP confirms direct REST binding plus functional KD phenotype with multiple differentiation markers, single lab with multiple orthogonal methods","pmids":["23242999"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Whole-cell patch-clamp in CHO cells; pharmacological PKA activation; co-expression with prestin; calcium chelation experiments; calmodulin/calcineurin inhibitors","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple electrophysiological conditions tested with pharmacological tools, single lab","pmids":["15660259"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Xenopus oocyte expression; two-electrode voltage clamp; kinase-dead mutant co-expression; KCNQ4 phosphorylation site mutagenesis","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation site plus kinase-dead control, single lab, Xenopus system","pmids":["16301825"],"is_preprint":false},{"year":2006,"finding":"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.","method":"RT-PCR from OHCs; Xenopus oocyte co-expression electrophysiology; two-electrode voltage clamp","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression confirmed by RT-PCR, functional co-expression with multiple KCNEs, single lab","pmids":["16914890"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Immunolabeling; freeze-fracture electron microscopy; Caspr knockout mouse analysis; ultrastructural analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with immunolocalization and ultrastructural analysis, direct localization with functional consequence, single lab","pmids":["19279247"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Patch-clamp electrophysiology; binding assays; mutagenesis of CaM-binding domain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — electrophysiology with mutagenesis and direct binding measurements, isoform-specific dissection, single lab with multiple methods","pmids":["26515070"],"is_preprint":false},{"year":2019,"finding":"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.","method":"X-ray crystallography; isothermal titration calorimetry; microscale thermophoresis; HSQC NMR spectroscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus ITC, NMR, and thermophoresis, multiple orthogonal biophysical methods, single lab","pmids":["30808708"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Whole-cell patch-clamp electrophysiology; CaM mutant co-expression; site-directed mutagenesis of S2-S3 loop","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology with systematic mutagenesis of both CaM and S2-S3 loop, mechanistic dissection, single lab","pmids":["33551832"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Xenopus oocyte expression; two-electrode voltage clamp; constitutively active and kinase-dead JAK2 mutants; brefeldin A treatment","journal":"The Journal of membrane biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — kinase-dead and constitutively active mutants with pharmacological inhibitor, single lab, Xenopus system without full mechanistic resolution","pmids":["23543186"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Whole-cell patch-clamp in HEK293 cells; osmotic challenge; pharmacological kinase/G protein modulators","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiology with multiple pharmacological dissections, cell volume functional readout, single lab","pmids":["14757214"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Patch-clamp; proximity ligation assay; co-immunoprecipitation; structured illumination microscopy; mass spectrometry; cholesterol depletion; morpholino knockdown; site-directed mutagenesis of dynein-binding site","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (mass spec, co-IP, PLA, super-resolution microscopy, electrophysiology, mutagenesis), single lab","pmids":["33533890"],"is_preprint":false},{"year":2012,"finding":"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.","method":"siRNA knockdown; isometric tension recording; patch-clamp of smooth muscle cells; quantitative PCR; immunohistochemistry","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with electrophysiology and tension recording, multiple methods, single lab","pmids":["22353613"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Western blot of mitochondrial fractions; immunocytochemistry with Mitotracker; Kv7.4 siRNA silencing; mitochondrial membrane potential and Ca2+ measurements","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with mitochondrial localization and functional assays, single lab, complements cardiac mitochondria data","pmids":["35085542"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Whole-cell patch-clamp in CHO cells; co-expression of wild-type and mutant KCNQ4; pharmacological rescue experiments","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic electrophysiology across multiple mutants with pharmacological rescue, single lab with multiple mutant/drug combinations","pmids":["21951272"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Patch-clamp electrophysiology of VTA DA neurons; pharmacological Gi/o and D2 receptor manipulation; redox pathway blockers; social defeat behavioral model","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiology with pharmacological pathway dissection and behavioral model, single lab","pmids":["31920557"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Heterologous cell expression; cell viability assays; autophagy inducer treatment","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell viability assays with pharmacological rescue, single lab, single method per finding","pmids":["34622280"],"is_preprint":false},{"year":2022,"finding":"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.","method":"CRISPR-Cas9 in vivo gene editing; dual-AAV delivery; ABR and DPOAE auditory testing; thallium ion live-cell imaging of OHC membrane potential","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vivo genetic intervention with multiple functional readouts (auditory physiology + novel live imaging), single lab with multiple orthogonal methods","pmids":["35265220"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Concatenated dimer/tetramer constructs expressed in smooth muscle cell line; whole-cell patch-clamp electrophysiology; pharmacological characterization","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — constrained stoichiometry approach in heterologous cells, single lab, no structural validation","pmids":["32903335"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Patch-clamp; wire myography; Western blot; traction force microscopy; in vivo smoke-exposure model; antioxidant treatment","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell biology and functional methods in human cells and mouse model, single lab","pmids":["33306938"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation; cell viability assays; ABR/DPOAE in vivo; cochlear histology; chromatin acetylation assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for HSP90β-KCNQ4 interaction plus in vivo functional data, single lab","pmids":["36982769"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Whole-cell patch-clamp of guinea pig OHCs; patch-clamp of KCNQ4-expressing CHO cells; nonstationary fluctuation analysis; pharmacological dissection","journal":"Journal of neurophysiology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — patch-clamp in both native OHCs and recombinant cells with single-channel analysis, single lab","pmids":["20147414"],"is_preprint":false}],"current_model":"KCNQ4 (Kv7.4) encodes a voltage-gated potassium channel that sets the resting membrane potential of cochlear outer hair cells via the I(K,n) current at the basolateral membrane, where its activity requires phosphatidylinositol(4,5)bisphosphate and is positively regulated by Gβγ subunits and PKA phosphorylation, and negatively regulated by Ca2+/calmodulin through the S2-S3 loop; pore-region disease mutations cause dominant hearing loss through dominant-negative inhibition and/or trafficking deficiency rescued by HSP90β chaperone activity; in the vasculature Kv7.4 forms functional Kv7.4/Kv7.5 heterotetramers that are regulated by KCNE4, PKC-dependent phosphorylation, and dynein-mediated membrane trafficking via caveolae, and are downregulated by miR-153 in hypertension; additionally, Kv7.4 is functional in mitochondria of cardiac and neuronal cells, and mediates auto-inhibition of VTA dopamine neurons through D2-receptor/Gi/o signaling."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1999,"claim":"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","pmids":["10025409"],"confidence":"High","gaps":["Did not resolve whether dominant-negative effect reflects loss of conductance or loss of surface trafficking","Native OHC consequences not yet shown"]},{"year":2000,"claim":"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","pmids":["10760300"],"confidence":"High","gaps":["Localization correlative rather than functional","Did not test channel necessity in vivo"]},{"year":2006,"claim":"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","pmids":["16437162"],"confidence":"High","gaps":["Mechanism linking chronic depolarization to selective degeneration not defined","No therapeutic intervention tested"]},{"year":2007,"claim":"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","pmids":["18030493","17561493"],"confidence":"High","gaps":["Chaperone machinery controlling trafficking not yet identified","Physiological isoform distribution across tissues unresolved"]},{"year":2013,"claim":"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","pmids":["23431407","23750663"],"confidence":"High","gaps":["HSP90β rescues surface expression but not conductance of pore mutants","Endogenous regulation of HSP90α vs HSP90β balance unclear"]},{"year":2011,"claim":"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","pmids":["22101641","21747056"],"confidence":"High","gaps":["Touch-sensitivity mechanism at the molecular level not detailed","Cause of vascular downregulation in hypertension not yet defined"]},{"year":2013,"claim":"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","pmids":["24297175","24558103","23408425"],"confidence":"High","gaps":["Exact subunit stoichiometry not resolved at this stage","Tissue-specific regulatory differences mechanistically incomplete"]},{"year":2010,"claim":"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","pmids":["20935082","20147414"],"confidence":"High","gaps":["Structural basis of PIP2 binding not defined","Salicylate binding site on the channel not mapped"]},{"year":2015,"claim":"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","pmids":["25941381","26503181","27981364"],"confidence":"High","gaps":["Structural mechanism of Gβγ-PIP2 synergy not established","Gβγ/PIP2 coupling shown pharmacologically without structural validation"]},{"year":2019,"claim":"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)","pmids":["30808708","33551832","26515070"],"confidence":"High","gaps":["Full-length channel structure with CaM not solved","How CaM regulation integrates with PIP2 occupancy unresolved"]},{"year":2021,"claim":"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","pmids":["33533890","27389411"],"confidence":"Medium","gaps":["In vivo contribution of dynein trafficking to blood pressure not tested","miR-153 luciferase/overexpression evidence from a single lab"]},{"year":2022,"claim":"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","pmids":["35265220","36982769","34622280"],"confidence":"High","gaps":["Durability and off-target effects of editing not fully characterized","Cytotoxicity of truncated variants and autophagy rescue shown only in heterologous cells"]},{"year":null,"claim":"How KCNQ4 mitochondrial channels are imported and gated, and how its diverse extra-cochlear roles (mitochondria, dopaminergic auto-inhibition, mechanotransduction) are integrated, remain unresolved.","evidence":"No direct experimental resolution in the available corpus","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,13,28]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8,30]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,29,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,13,28]}],"complexes":["Kv7.4/Kv7.5 heterotetramer"],"partners":["KCNQ5","CALM1","KCNE4","HSP90AB1","CAV1","CNTNAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56696","full_name":"Potassium voltage-gated channel subfamily KQT member 4","aliases":["KQT-like 4","Potassium channel subunit alpha KvLQT4","Voltage-gated potassium channel subunit Kv7.4"],"length_aa":695,"mass_kda":77.1,"function":"Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of sensory cells excitability in the cochlea (PubMed:10025409, PubMed:34767770). KCNQ4/Kv7.4 channel is composed of 4 pore-forming subunits assembled as tetramers (PubMed:34767770). Promotes the outflow of potassium ions in the repolarization phase of action potential which plays a role in regulating membrane potential of excitable cells (PubMed:10025409, PubMed:11245603, PubMed:34767770). The channel conducts a slowly activating and deactivating current (PubMed:10025409, PubMed:11245603). Current often shows some inward rectification at positive potentials (PubMed:10025409). Channel may be selectively permeable in vitro to other cations besides potassium, in decreasing order of affinity K(+) = Rb(+) > Cs(+) > Na(+) (PubMed:10025409). Important for normal physiological function of inner ear such as sensory perception of sound (PubMed:10025409, PubMed:10369879)","subcellular_location":"Basal cell membrane","url":"https://www.uniprot.org/uniprotkb/P56696/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNQ4","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNQ4","total_profiled":1310},"omim":[{"mim_id":"620283","title":"DEAFNESS, AUTOSOMAL DOMINANT 88; DFNA88","url":"https://www.omim.org/entry/620283"},{"mim_id":"612644","title":"DEAFNESS, AUTOSOMAL DOMINANT 2B; DFNA2B","url":"https://www.omim.org/entry/612644"},{"mim_id":"607357","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 5; KCNQ5","url":"https://www.omim.org/entry/607357"},{"mim_id":"604433","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 3; KCNE3","url":"https://www.omim.org/entry/604433"},{"mim_id":"603537","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 4; KCNQ4","url":"https://www.omim.org/entry/603537"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":3.7}],"url":"https://www.proteinatlas.org/search/KCNQ4"},"hgnc":{"alias_symbol":["Kv7.4"],"prev_symbol":["DFNA2"]},"alphafold":{"accession":"P56696","domains":[{"cath_id":"1.20.120","chopping":"75-220","consensus_level":"high","plddt":84.4144,"start":75,"end":220},{"cath_id":"1.10.287.70","chopping":"222-375_524-555","consensus_level":"medium","plddt":88.954,"start":222,"end":555}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56696","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56696-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56696-F1-predicted_aligned_error_v6.png","plddt_mean":65.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNQ4","jax_strain_url":"https://www.jax.org/strain/search?query=KCNQ4"},"sequence":{"accession":"P56696","fasta_url":"https://rest.uniprot.org/uniprotkb/P56696.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56696/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56696"}},"corpus_meta":[{"pmid":"10025409","id":"PMC_10025409","title":"KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10025409","citation_count":690,"is_preprint":false},{"pmid":"10760300","id":"PMC_10760300","title":"KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10760300","citation_count":344,"is_preprint":false},{"pmid":"16437162","id":"PMC_16437162","title":"Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16437162","citation_count":217,"is_preprint":false},{"pmid":"10369879","id":"PMC_10369879","title":"Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10369879","citation_count":139,"is_preprint":false},{"pmid":"21747056","id":"PMC_21747056","title":"Downregulation of Kv7.4 channel activity in primary and secondary hypertension.","date":"2011","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/21747056","citation_count":134,"is_preprint":false},{"pmid":"16207888","id":"PMC_16207888","title":"Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16207888","citation_count":105,"is_preprint":false},{"pmid":"22353613","id":"PMC_22353613","title":"Reduced KCNQ4-encoded voltage-dependent potassium channel activity underlies impaired β-adrenoceptor-mediated relaxation of renal arteries in hypertension.","date":"2012","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/22353613","citation_count":99,"is_preprint":false},{"pmid":"22101641","id":"PMC_22101641","title":"KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man.","date":"2011","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22101641","citation_count":89,"is_preprint":false},{"pmid":"16917933","id":"PMC_16917933","title":"KCNQ4: a gene for age-related hearing impairment?","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16917933","citation_count":85,"is_preprint":false},{"pmid":"24558103","id":"PMC_24558103","title":"Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity.","date":"2014","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24558103","citation_count":81,"is_preprint":false},{"pmid":"11042367","id":"PMC_11042367","title":"Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2.","date":"2000","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11042367","citation_count":79,"is_preprint":false},{"pmid":"36859185","id":"PMC_36859185","title":"LncRNA-BC069792 suppresses tumor progression by targeting KCNQ4 in breast cancer.","date":"2023","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36859185","citation_count":68,"is_preprint":false},{"pmid":"26718475","id":"PMC_26718475","title":"Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection.","date":"2015","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/26718475","citation_count":67,"is_preprint":false},{"pmid":"24297175","id":"PMC_24297175","title":"Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24297175","citation_count":62,"is_preprint":false},{"pmid":"26503181","id":"PMC_26503181","title":"Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone.","date":"2015","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26503181","citation_count":62,"is_preprint":false},{"pmid":"25941381","id":"PMC_25941381","title":"G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25941381","citation_count":57,"is_preprint":false},{"pmid":"20876743","id":"PMC_20876743","title":"Diclofenac distinguishes among homomeric and heteromeric potassium channels composed of KCNQ4 and KCNQ5 subunits.","date":"2010","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20876743","citation_count":52,"is_preprint":false},{"pmid":"10571947","id":"PMC_10571947","title":"Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss.","date":"1999","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/10571947","citation_count":50,"is_preprint":false},{"pmid":"23717403","id":"PMC_23717403","title":"Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23717403","citation_count":50,"is_preprint":false},{"pmid":"16914890","id":"PMC_16914890","title":"Functional coassembly of KCNQ4 with KCNE-beta- subunits in Xenopus oocytes.","date":"2006","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16914890","citation_count":48,"is_preprint":false},{"pmid":"10925378","id":"PMC_10925378","title":"Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region.","date":"2000","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10925378","citation_count":47,"is_preprint":false},{"pmid":"20935082","id":"PMC_20935082","title":"Aminoglycosides inhibit KCNQ4 channels in cochlear outer hair cells via depletion of phosphatidylinositol(4,5)bisphosphate.","date":"2010","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20935082","citation_count":47,"is_preprint":false},{"pmid":"35265220","id":"PMC_35265220","title":"In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/35265220","citation_count":45,"is_preprint":false},{"pmid":"27389411","id":"PMC_27389411","title":"MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension.","date":"2016","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/27389411","citation_count":45,"is_preprint":false},{"pmid":"11915881","id":"PMC_11915881","title":"Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family.","date":"2002","source":"The Annals of otology, rhinology, and laryngology","url":"https://pubmed.ncbi.nlm.nih.gov/11915881","citation_count":44,"is_preprint":false},{"pmid":"16596322","id":"PMC_16596322","title":"A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation.","date":"2006","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16596322","citation_count":44,"is_preprint":false},{"pmid":"23242999","id":"PMC_23242999","title":"Specification of skeletal muscle differentiation by repressor element-1 silencing transcription factor (REST)-regulated Kv7.4 potassium channels.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23242999","citation_count":43,"is_preprint":false},{"pmid":"12112653","id":"PMC_12112653","title":"A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment.","date":"2002","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/12112653","citation_count":42,"is_preprint":false},{"pmid":"22319145","id":"PMC_22319145","title":"The voltage-gated potassium channel subfamily KQT member 4 (KCNQ4) displays parallel evolution in echolocating bats.","date":"2011","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/22319145","citation_count":42,"is_preprint":false},{"pmid":"21951272","id":"PMC_21951272","title":"Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers.","date":"2012","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21951272","citation_count":41,"is_preprint":false},{"pmid":"18030493","id":"PMC_18030493","title":"A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression.","date":"2007","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18030493","citation_count":40,"is_preprint":false},{"pmid":"23408425","id":"PMC_23408425","title":"Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23408425","citation_count":38,"is_preprint":false},{"pmid":"17561493","id":"PMC_17561493","title":"Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17561493","citation_count":38,"is_preprint":false},{"pmid":"22046315","id":"PMC_22046315","title":"Parallel evolution of KCNQ4 in echolocating bats.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22046315","citation_count":38,"is_preprint":false},{"pmid":"15660259","id":"PMC_15660259","title":"Regulation of the voltage-gated potassium channel KCNQ4 in the auditory pathway.","date":"2005","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15660259","citation_count":37,"is_preprint":false},{"pmid":"18941426","id":"PMC_18941426","title":"Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus.","date":"2008","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18941426","citation_count":37,"is_preprint":false},{"pmid":"23750663","id":"PMC_23750663","title":"Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss.","date":"2013","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23750663","citation_count":35,"is_preprint":false},{"pmid":"33306938","id":"PMC_33306938","title":"Cigarette Smoke Directly Promotes Pulmonary Arterial Remodeling and Kv7.4 Channel Dysfunction.","date":"2021","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33306938","citation_count":34,"is_preprint":false},{"pmid":"11556850","id":"PMC_11556850","title":"Speech recognition scores related to age and degree of hearing impairment in DFNA2/KCNQ4 and DFNA9/COCH.","date":"2001","source":"Archives of otolaryngology--head & neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/11556850","citation_count":34,"is_preprint":false},{"pmid":"17292869","id":"PMC_17292869","title":"Developmental expression of Kcnq4 in vestibular neurons and neurosensory epithelia.","date":"2007","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17292869","citation_count":33,"is_preprint":false},{"pmid":"16301825","id":"PMC_16301825","title":"Regulation of KCNQ4 potassium channel prepulse dependence and current amplitude by SGK1 in Xenopus oocytes.","date":"2005","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16301825","citation_count":32,"is_preprint":false},{"pmid":"19279247","id":"PMC_19279247","title":"The septate junction protein caspr is required for structural support and retention of KCNQ4 at calyceal synapses of vestibular hair cells.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19279247","citation_count":32,"is_preprint":false},{"pmid":"11450843","id":"PMC_11450843","title":"Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese.","date":"2001","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11450843","citation_count":32,"is_preprint":false},{"pmid":"15699719","id":"PMC_15699719","title":"Phenotype determination guides swift genotyping of a DFNA2/KCNQ4 family with a hot spot mutation (W276S).","date":"2005","source":"Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","url":"https://pubmed.ncbi.nlm.nih.gov/15699719","citation_count":31,"is_preprint":false},{"pmid":"23431407","id":"PMC_23431407","title":"Distinct roles of molecular chaperones HSP90α and HSP90β in the biogenesis of KCNQ4 channels.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23431407","citation_count":30,"is_preprint":false},{"pmid":"17033161","id":"PMC_17033161","title":"Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan.","date":"2006","source":"Audiology & neuro-otology","url":"https://pubmed.ncbi.nlm.nih.gov/17033161","citation_count":28,"is_preprint":false},{"pmid":"33801540","id":"PMC_33801540","title":"Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33801540","citation_count":24,"is_preprint":false},{"pmid":"18797286","id":"PMC_18797286","title":"KCNQ4 mutations associated with nonsyndromic progressive sensorineural hearing loss.","date":"2008","source":"Current opinion in otolaryngology & head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/18797286","citation_count":24,"is_preprint":false},{"pmid":"30413759","id":"PMC_30413759","title":"Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30413759","citation_count":24,"is_preprint":false},{"pmid":"25116015","id":"PMC_25116015","title":"Targeted high-throughput sequencing identifies pathogenic mutations in KCNQ4 in two large Chinese families with autosomal dominant hearing loss.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25116015","citation_count":24,"is_preprint":false},{"pmid":"14757214","id":"PMC_14757214","title":"Modulation of KCNQ4 channel activity by changes in cell volume.","date":"2004","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/14757214","citation_count":24,"is_preprint":false},{"pmid":"34316018","id":"PMC_34316018","title":"Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss.","date":"2021","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34316018","citation_count":23,"is_preprint":false},{"pmid":"31434872","id":"PMC_31434872","title":"Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment.","date":"2019","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31434872","citation_count":23,"is_preprint":false},{"pmid":"20147414","id":"PMC_20147414","title":"Effect of salicylate on KCNQ4 of the guinea pig outer hair cell.","date":"2010","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/20147414","citation_count":23,"is_preprint":false},{"pmid":"21242547","id":"PMC_21242547","title":"Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene.","date":"2011","source":"Archives of otolaryngology--head & neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/21242547","citation_count":22,"is_preprint":false},{"pmid":"20832469","id":"PMC_20832469","title":"Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20832469","citation_count":22,"is_preprint":false},{"pmid":"30556268","id":"PMC_30556268","title":"A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30556268","citation_count":21,"is_preprint":false},{"pmid":"12851819","id":"PMC_12851819","title":"Voltage-independent KCNQ4 currents induced by (+/-)BMS-204352.","date":"2003","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12851819","citation_count":21,"is_preprint":false},{"pmid":"23543186","id":"PMC_23543186","title":"Downregulation of KCNQ4 by Janus kinase 2.","date":"2013","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/23543186","citation_count":20,"is_preprint":false},{"pmid":"33533890","id":"PMC_33533890","title":"Dynein regulates Kv7.4 channel trafficking from the cell membrane.","date":"2021","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33533890","citation_count":18,"is_preprint":false},{"pmid":"31995783","id":"PMC_31995783","title":"Molecular basis and restoration of function deficiencies of Kv7.4 variants associated with inherited hearing loss.","date":"2020","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/31995783","citation_count":17,"is_preprint":false},{"pmid":"29775679","id":"PMC_29775679","title":"Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.","date":"2018","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29775679","citation_count":16,"is_preprint":false},{"pmid":"37009795","id":"PMC_37009795","title":"Overlooked KCNQ4 variants augment the risk of hearing loss.","date":"2023","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37009795","citation_count":15,"is_preprint":false},{"pmid":"27981364","id":"PMC_27981364","title":"Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity.","date":"2016","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27981364","citation_count":14,"is_preprint":false},{"pmid":"21782781","id":"PMC_21782781","title":"Identification of novel KCNQ4 openers by a high-throughput fluorescence-based thallium flux assay.","date":"2011","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21782781","citation_count":14,"is_preprint":false},{"pmid":"26515070","id":"PMC_26515070","title":"Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26515070","citation_count":14,"is_preprint":false},{"pmid":"31920557","id":"PMC_31920557","title":"Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area.","date":"2019","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31920557","citation_count":14,"is_preprint":false},{"pmid":"30808708","id":"PMC_30808708","title":"A mutually induced conformational fit underlies Ca2+-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K+ channels.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30808708","citation_count":14,"is_preprint":false},{"pmid":"36140355","id":"PMC_36140355","title":"The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36140355","citation_count":13,"is_preprint":false},{"pmid":"34828318","id":"PMC_34828318","title":"A KCNQ4 c.546C>G Genetic Variant Associated with Late Onset Non-Syndromic Hearing Loss in a Taiwanese Population.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34828318","citation_count":13,"is_preprint":false},{"pmid":"35038006","id":"PMC_35038006","title":"AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss.","date":"2022","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35038006","citation_count":13,"is_preprint":false},{"pmid":"35760561","id":"PMC_35760561","title":"Proactive functional classification of all possible missense single-nucleotide variants in KCNQ4.","date":"2022","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/35760561","citation_count":13,"is_preprint":false},{"pmid":"27081546","id":"PMC_27081546","title":"A novel KCNQ4 mutation and a private IMMP2L-DOCK4 duplication segregating with nonsyndromic hearing loss in a Brazilian family.","date":"2015","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/27081546","citation_count":12,"is_preprint":false},{"pmid":"31126177","id":"PMC_31126177","title":"Novel Mutations in KCNQ4, LHFPL5 and COCH Genes in Iranian Families with Hearing Impairment.","date":"2019","source":"Archives of Iranian medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31126177","citation_count":12,"is_preprint":false},{"pmid":"26969140","id":"PMC_26969140","title":"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.","date":"2016","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26969140","citation_count":12,"is_preprint":false},{"pmid":"26036578","id":"PMC_26036578","title":"A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26036578","citation_count":11,"is_preprint":false},{"pmid":"23443030","id":"PMC_23443030","title":"Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL.","date":"2013","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/23443030","citation_count":11,"is_preprint":false},{"pmid":"21585154","id":"PMC_21585154","title":"Audioprofile-directed successful mutation analysis in a DFNA2/KCNQ4 (p.Leu274His) family.","date":"2011","source":"The Annals of otology, rhinology, and laryngology","url":"https://pubmed.ncbi.nlm.nih.gov/21585154","citation_count":10,"is_preprint":false},{"pmid":"22420747","id":"PMC_22420747","title":"In silico modeling of the pore region of a KCNQ4 missense mutant from a patient with hearing loss.","date":"2012","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/22420747","citation_count":10,"is_preprint":false},{"pmid":"35599357","id":"PMC_35599357","title":"A humanized murine model, demonstrating dominant progressive hearing loss caused by a novel KCNQ4 mutation (p.G228D) from a large Chinese family.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35599357","citation_count":9,"is_preprint":false},{"pmid":"30153627","id":"PMC_30153627","title":"Genetic variation in KCNQ4 gene is associated with susceptibility to noise-induced hearing loss in a Chinese population.","date":"2018","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30153627","citation_count":9,"is_preprint":false},{"pmid":"28340560","id":"PMC_28340560","title":"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.","date":"2017","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28340560","citation_count":9,"is_preprint":false},{"pmid":"35085542","id":"PMC_35085542","title":"Kv7.4 channels regulate potassium permeability in neuronal mitochondria.","date":"2022","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35085542","citation_count":8,"is_preprint":false},{"pmid":"34479475","id":"PMC_34479475","title":"miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model.","date":"2021","source":"The journal of physiological sciences : JPS","url":"https://pubmed.ncbi.nlm.nih.gov/34479475","citation_count":8,"is_preprint":false},{"pmid":"33846771","id":"PMC_33846771","title":"A novel KCNQ4 gene variant (c.857A>G; p.Tyr286Cys) in an extended family with non‑syndromic deafness 2A.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33846771","citation_count":8,"is_preprint":false},{"pmid":"23089626","id":"PMC_23089626","title":"BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells.","date":"2012","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/23089626","citation_count":8,"is_preprint":false},{"pmid":"33551832","id":"PMC_33551832","title":"The S2-S3 Loop of Kv7.4 Channels Is Essential for Calmodulin Regulation of Channel Activation.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33551832","citation_count":8,"is_preprint":false},{"pmid":"23399560","id":"PMC_23399560","title":"Moderate hearing loss associated with a novel KCNQ4 non-truncating mutation located near the N-terminus of the pore helix.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23399560","citation_count":8,"is_preprint":false},{"pmid":"34381336","id":"PMC_34381336","title":"Alteration of Mesopontine Cholinergic Function by the Lack of KCNQ4 Subunit.","date":"2021","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34381336","citation_count":7,"is_preprint":false},{"pmid":"24655070","id":"PMC_24655070","title":"A Japanese family showing high-frequency hearing loss with KCNQ4 and TECTA mutations.","date":"2014","source":"Acta oto-laryngologica","url":"https://pubmed.ncbi.nlm.nih.gov/24655070","citation_count":7,"is_preprint":false},{"pmid":"34622280","id":"PMC_34622280","title":"Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss.","date":"2021","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/34622280","citation_count":6,"is_preprint":false},{"pmid":"36982769","id":"PMC_36982769","title":"Valproic Acid Inhibits Progressive Hereditary Hearing Loss in a KCNQ4 Variant Model through HDAC1 Suppression.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36982769","citation_count":5,"is_preprint":false},{"pmid":"32903335","id":"PMC_32903335","title":"Heteromeric Channels Formed From Alternating Kv7.4 and Kv7.5 α-Subunits Display Biophysical, Regulatory, and Pharmacological Characteristics of Smooth Muscle M-Currents.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32903335","citation_count":5,"is_preprint":false},{"pmid":"34863875","id":"PMC_34863875","title":"Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34863875","citation_count":4,"is_preprint":false},{"pmid":"19701239","id":"PMC_19701239","title":"Functional study of the effect of phosphatase inhibitors on KCNQ4 channels expressed in Xenopus oocytes.","date":"2009","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/19701239","citation_count":4,"is_preprint":false},{"pmid":"16876114","id":"PMC_16876114","title":"Studies of the effect of ionomycin on the KCNQ4 channel expressed in Xenopus oocytes.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16876114","citation_count":4,"is_preprint":false},{"pmid":"36789839","id":"PMC_36789839","title":"KCNQ4 potassium channel subunit deletion leads to exaggerated acoustic startle reflex in mice.","date":"2023","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/36789839","citation_count":3,"is_preprint":false},{"pmid":"37962101","id":"PMC_37962101","title":"Natural History of KCNQ4 p.G285S Related Hearing Loss, Construction of iPSC and Mouse Model.","date":"2023","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/37962101","citation_count":3,"is_preprint":false},{"pmid":"33093272","id":"PMC_33093272","title":"The agonistic action of URO-K10 on Kv7.4 and 7.5 channels is attenuated by co-expression of KCNE4 ancillary subunit.","date":"2020","source":"The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33093272","citation_count":3,"is_preprint":false},{"pmid":"33367117","id":"PMC_33367117","title":"Molecular simulation of the Kv7.4[ΔS269] mutant channel reveals that ion conduction in the cavity is perturbed due to hydrophobic gating.","date":"2020","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/33367117","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52728,"output_tokens":10413,"usd":0.15719,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21019,"output_tokens":4376,"usd":0.107247,"stage2_stop_reason":"end_turn"},"total_usd":0.264437,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression with whole-cell patch-clamp electrophysiology; dominant-negative co-expression assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro electrophysiology with mutagenesis, foundational paper replicated across multiple subsequent studies\",\n      \"pmids\": [\"10025409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry with specific antibodies; subcellular fractionation/localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with specific antibodies, replicated in multiple subsequent studies, tied to functional current identity\",\n      \"pmids\": [\"10760300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout and dominant-negative knock-in mouse models; in vivo auditory function (ABR/DPOAE); patch-clamp of isolated OHCs; histological analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic loss-of-function with multiple orthogonal phenotypic readouts (electrophysiology, histology, auditory function), confirmed in two alleles\",\n      \"pmids\": [\"16437162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology of splice variants expressed in heterologous cells; dominant-negative co-expression; calmodulin modulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with multiple isoforms and mutagenesis-based dominant-negative approach, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17561493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus oocyte electrophysiology; non-permeabilized cell surface immunolabeling (HA-tagged KCNQ4); co-expression dominant-negative assay in oocytes\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — electrophysiology plus direct cell-surface labeling, two orthogonal methods, single lab\",\n      \"pmids\": [\"18030493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp of rat OHCs and recombinant KCNQ channels; fluorescence imaging of cellular PI(4,5)P2; pharmacological rescue with KCNQ openers\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — patch-clamp with fluorescence imaging of PI(4,5)P2, multiple aminoglycosides tested, mechanistic link confirmed by PI(4,5)P2 availability manipulation\",\n      \"pmids\": [\"20935082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Single-unit electrophysiological recordings from Kcnq4−/− mice and DFNA2 knock-in mice; immunohistochemistry; vibrotactile testing in human DFNA2 subjects\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo single-unit recordings in multiple genetic models plus human psychophysics, replicated across mouse and human\",\n      \"pmids\": [\"22101641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative PCR; Western blot; isometric tension recording; patch-clamp of isolated myocytes; pharmacological Kv7 activators/blockers\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (PCR, WB, electrophysiology, myography), replicated in two independent hypertension models\",\n      \"pmids\": [\"21747056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (immunogold EM, WB, functional flux assays, RNAi, whole-heart preparation), single lab\",\n      \"pmids\": [\"26718475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Proximity ligation assay; dominant-negative patch-clamp; inducible PKCα translocation system; phosphorylation assay; whole-cell electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proximity ligation assay for heteromer detection plus dominant-negative electrophysiology and phosphorylation assays, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"24297175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Immunolocalization in Kcnq4−/− and dominant-negative knock-in mice; whole-cell recordings of vestibular hair cells; vestibulo-ocular reflex testing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic models with direct electrophysiology and functional vestibular testing, multiple genotypes compared\",\n      \"pmids\": [\"23408425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Proximity ligation assay; siRNA knockdown; isometric and isobaric myography; pharmacological Kv7 blockers\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation plus siRNA knockdown with functional myography, multiple orthogonal approaches\",\n      \"pmids\": [\"24558103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics; reciprocal co-immunoprecipitation; Western blot; immunofluorescence; siRNA/overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP confirmed by proteomics, functional rescue with chaperone manipulation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23431407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence; Western blot; patch-clamp electrophysiology; co-IP for tetramer assembly\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — electrophysiology plus surface immunolabeling across multiple mutants, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23750663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Proximity ligation assay; HEK cell co-expression electrophysiology; morpholino knockdown; quantitative PCR; isometric tension recording\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation, electrophysiology, morpholino KD with functional myography, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26503181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell and excised patch-clamp; proximity ligation assay; pharmacological Gβγ inhibitors; isometric tension recording\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — excised patch single-channel recordings plus proximity ligation and functional vascular assays, multiple orthogonal methods\",\n      \"pmids\": [\"25941381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp in HEK cells stably expressing Kv7.4; pharmacological PIP2 depletion and Gβγ inhibition\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological approach in single expression system, single lab, no structural validation\",\n      \"pmids\": [\"27981364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay; quantitative PCR; Western blot; isometric tension recording; miR-153 overexpression in arteries\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay confirms direct 3'UTR targeting, functional vascular experiments, single lab\",\n      \"pmids\": [\"27389411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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).\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); RNA interference; REST overexpression; differentiation marker Western blot/immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP confirms direct REST binding plus functional KD phenotype with multiple differentiation markers, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23242999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp in CHO cells; pharmacological PKA activation; co-expression with prestin; calcium chelation experiments; calmodulin/calcineurin inhibitors\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple electrophysiological conditions tested with pharmacological tools, single lab\",\n      \"pmids\": [\"15660259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus oocyte expression; two-electrode voltage clamp; kinase-dead mutant co-expression; KCNQ4 phosphorylation site mutagenesis\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation site plus kinase-dead control, single lab, Xenopus system\",\n      \"pmids\": [\"16301825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR from OHCs; Xenopus oocyte co-expression electrophysiology; two-electrode voltage clamp\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression confirmed by RT-PCR, functional co-expression with multiple KCNEs, single lab\",\n      \"pmids\": [\"16914890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Immunolabeling; freeze-fracture electron microscopy; Caspr knockout mouse analysis; ultrastructural analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with immunolocalization and ultrastructural analysis, direct localization with functional consequence, single lab\",\n      \"pmids\": [\"19279247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology; binding assays; mutagenesis of CaM-binding domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — electrophysiology with mutagenesis and direct binding measurements, isoform-specific dissection, single lab with multiple methods\",\n      \"pmids\": [\"26515070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography; isothermal titration calorimetry; microscale thermophoresis; HSQC NMR spectroscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus ITC, NMR, and thermophoresis, multiple orthogonal biophysical methods, single lab\",\n      \"pmids\": [\"30808708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology; CaM mutant co-expression; site-directed mutagenesis of S2-S3 loop\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology with systematic mutagenesis of both CaM and S2-S3 loop, mechanistic dissection, single lab\",\n      \"pmids\": [\"33551832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus oocyte expression; two-electrode voltage clamp; constitutively active and kinase-dead JAK2 mutants; brefeldin A treatment\",\n      \"journal\": \"The Journal of membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — kinase-dead and constitutively active mutants with pharmacological inhibitor, single lab, Xenopus system without full mechanistic resolution\",\n      \"pmids\": [\"23543186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp in HEK293 cells; osmotic challenge; pharmacological kinase/G protein modulators\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiology with multiple pharmacological dissections, cell volume functional readout, single lab\",\n      \"pmids\": [\"14757214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp; proximity ligation assay; co-immunoprecipitation; structured illumination microscopy; mass spectrometry; cholesterol depletion; morpholino knockdown; site-directed mutagenesis of dynein-binding site\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (mass spec, co-IP, PLA, super-resolution microscopy, electrophysiology, mutagenesis), single lab\",\n      \"pmids\": [\"33533890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; isometric tension recording; patch-clamp of smooth muscle cells; quantitative PCR; immunohistochemistry\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with electrophysiology and tension recording, multiple methods, single lab\",\n      \"pmids\": [\"22353613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot of mitochondrial fractions; immunocytochemistry with Mitotracker; Kv7.4 siRNA silencing; mitochondrial membrane potential and Ca2+ measurements\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with mitochondrial localization and functional assays, single lab, complements cardiac mitochondria data\",\n      \"pmids\": [\"35085542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp in CHO cells; co-expression of wild-type and mutant KCNQ4; pharmacological rescue experiments\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic electrophysiology across multiple mutants with pharmacological rescue, single lab with multiple mutant/drug combinations\",\n      \"pmids\": [\"21951272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology of VTA DA neurons; pharmacological Gi/o and D2 receptor manipulation; redox pathway blockers; social defeat behavioral model\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiology with pharmacological pathway dissection and behavioral model, single lab\",\n      \"pmids\": [\"31920557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous cell expression; cell viability assays; autophagy inducer treatment\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell viability assays with pharmacological rescue, single lab, single method per finding\",\n      \"pmids\": [\"34622280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 in vivo gene editing; dual-AAV delivery; ABR and DPOAE auditory testing; thallium ion live-cell imaging of OHC membrane potential\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vivo genetic intervention with multiple functional readouts (auditory physiology + novel live imaging), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35265220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Concatenated dimer/tetramer constructs expressed in smooth muscle cell line; whole-cell patch-clamp electrophysiology; pharmacological characterization\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — constrained stoichiometry approach in heterologous cells, single lab, no structural validation\",\n      \"pmids\": [\"32903335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp; wire myography; Western blot; traction force microscopy; in vivo smoke-exposure model; antioxidant treatment\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell biology and functional methods in human cells and mouse model, single lab\",\n      \"pmids\": [\"33306938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; cell viability assays; ABR/DPOAE in vivo; cochlear histology; chromatin acetylation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for HSP90β-KCNQ4 interaction plus in vivo functional data, single lab\",\n      \"pmids\": [\"36982769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp of guinea pig OHCs; patch-clamp of KCNQ4-expressing CHO cells; nonstationary fluctuation analysis; pharmacological dissection\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — patch-clamp in both native OHCs and recombinant cells with single-channel analysis, single lab\",\n      \"pmids\": [\"20147414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNQ4 (Kv7.4) encodes a voltage-gated potassium channel that sets the resting membrane potential of cochlear outer hair cells via the I(K,n) current at the basolateral membrane, where its activity requires phosphatidylinositol(4,5)bisphosphate and is positively regulated by Gβγ subunits and PKA phosphorylation, and negatively regulated by Ca2+/calmodulin through the S2-S3 loop; pore-region disease mutations cause dominant hearing loss through dominant-negative inhibition and/or trafficking deficiency rescued by HSP90β chaperone activity; in the vasculature Kv7.4 forms functional Kv7.4/Kv7.5 heterotetramers that are regulated by KCNE4, PKC-dependent phosphorylation, and dynein-mediated membrane trafficking via caveolae, and are downregulated by miR-153 in hypertension; additionally, Kv7.4 is functional in mitochondria of cardiac and neuronal cells, and mediates auto-inhibition of VTA dopamine neurons through D2-receptor/Gi/o signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #2]. 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 HSP90\\u03b2 chaperone activity [#4, #12, #13]. Channel gating is governed by phosphoinositide and Ca2+ signaling: KCNQ4 requires PI(4,5)P2 for activity, G\\u03b2\\u03b3 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 [#5, #15, #16, #23, #24, #25]. C-terminal alternative splicing generates isoforms differing in voltage dependence and calmodulin regulation [#3], and additional kinase inputs (PKA, SGK1) shift activation [#19, #20]. Beyond hearing, KCNQ4 is expressed in type I vestibular afferent calyces where it is clustered by Caspr [#10, #22], in cutaneous mechanoreceptors where it tunes touch sensitivity [#6], 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 \\u03b2-adrenoceptor- and CGRP-dependent vasodilation that is impaired in hypertension [#7, #9, #11, #14, #28, #29, #17]. KCNQ4 is also functional in cardiac and neuronal mitochondria, regulating membrane potential and Ca2+ uptake [#8, #30], and contributes to D2-receptor/Gi/o-mediated auto-inhibition of VTA dopamine neurons [#32]. 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 [#34].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established why KCNQ4 mutations cause dominant rather than recessive deafness by showing pore mutations act dominant-negatively on co-assembled wild-type channels.\",\n      \"evidence\": \"Heterologous expression with whole-cell patch-clamp and dominant-negative co-expression assay\",\n      \"pmids\": [\"10025409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether dominant-negative effect reflects loss of conductance or loss of surface trafficking\", \"Native OHC consequences not yet shown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunohistochemistry with specific antibodies and subcellular localization\",\n      \"pmids\": [\"10760300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Localization correlative rather than functional\", \"Did not test channel necessity in vivo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated in vivo that KCNQ4 maintains OHC membrane potential and survival, defining the cellular basis of progressive hearing loss.\",\n      \"evidence\": \"Knockout and dominant-negative knock-in mice with auditory physiology, OHC patch-clamp, and histology\",\n      \"pmids\": [\"16437162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking chronic depolarization to selective degeneration not defined\", \"No therapeutic intervention tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Refined the dominant-negative mechanism by showing pore mutations primarily reduce surface trafficking, and that C-terminal splicing diversifies channel gating and calmodulin regulation.\",\n      \"evidence\": \"Oocyte and heterologous electrophysiology, surface immunolabeling of HA-tagged channels, and splice-variant characterization\",\n      \"pmids\": [\"18030493\", \"17561493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chaperone machinery controlling trafficking not yet identified\", \"Physiological isoform distribution across tissues unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the chaperone network controlling KCNQ4 biogenesis and showed HSP90\\u03b2 can rescue trafficking-deficient disease mutants, defining a druggable proteostasis axis.\",\n      \"evidence\": \"Proteomics, reciprocal co-IP, and overexpression/siRNA with surface-expression rescue of DFNA2 mutants\",\n      \"pmids\": [\"23431407\", \"23750663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HSP90\\u03b2 rescues surface expression but not conductance of pore mutants\", \"Endogenous regulation of HSP90\\u03b1 vs HSP90\\u03b2 balance unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended KCNQ4 function beyond the cochlea to cutaneous mechanoreceptors and to vascular smooth muscle, where its downregulation impairs vasorelaxation in hypertension.\",\n      \"evidence\": \"Single-unit recordings in mouse models plus human psychophysics; qPCR/Western/myography in hypertensive rat and angiotensin II models\",\n      \"pmids\": [\"22101641\", \"21747056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Touch-sensitivity mechanism at the molecular level not detailed\", \"Cause of vascular downregulation in hypertension not yet defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proximity ligation, dominant-negative electrophysiology, siRNA, myography, and immunolocalization in genetic models\",\n      \"pmids\": [\"24297175\", \"24558103\", \"23408425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact subunit stoichiometry not resolved at this stage\", \"Tissue-specific regulatory differences mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed PI(4,5)P2 as an obligatory cofactor for KCNQ4 activity, mechanistically explaining aminoglycoside and salicylate ototoxicity.\",\n      \"evidence\": \"OHC and recombinant patch-clamp with PI(4,5)P2 imaging and pharmacological dissection\",\n      \"pmids\": [\"20935082\", \"20147414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PIP2 binding not defined\", \"Salicylate binding site on the channel not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified G\\u03b2\\u03b3 and KCNE4 as positive regulators of Kv7.4 in vasculature, with G\\u03b2\\u03b3 acting by potentiating PIP2 sensitivity.\",\n      \"evidence\": \"Excised-patch single-channel recordings, proximity ligation, HEK co-expression, morpholino knockdown, and tension recording\",\n      \"pmids\": [\"25941381\", \"26503181\", \"27981364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of G\\u03b2\\u03b3-PIP2 synergy not established\", \"G\\u03b2\\u03b3/PIP2 coupling shown pharmacologically without structural validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography, ITC, NMR, thermophoresis (2019); systematic CaM and S2-S3 loop mutagenesis with patch-clamp (2021); isoform-specific CaM dissection (2015)\",\n      \"pmids\": [\"30808708\", \"33551832\", \"26515070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length channel structure with CaM not solved\", \"How CaM regulation integrates with PIP2 occupancy unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined trafficking control of vascular Kv7.4 by caveolin-1/dynein and post-transcriptional suppression by miR-153, linking channel surface abundance to hypertension.\",\n      \"evidence\": \"Co-IP, proximity ligation, super-resolution microscopy, mass spectrometry, dynein-site mutagenesis; luciferase 3'UTR reporter and miR-153 overexpression in arteries\",\n      \"pmids\": [\"33533890\", \"27389411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution of dynein trafficking to blood pressure not tested\", \"miR-153 luciferase/overexpression evidence from a single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo dual-AAV CRISPR-Cas9 editing with ABR/DPOAE and thallium live-cell imaging; complementary VPA/HSP90\\u03b2 and autophagy-inducer rescue studies\",\n      \"pmids\": [\"35265220\", \"36982769\", \"34622280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and off-target effects of editing not fully characterized\", \"Cytotoxicity of truncated variants and autophagy rescue shown only in heterologous cells\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KCNQ4 mitochondrial channels are imported and gated, and how its diverse extra-cochlear roles (mitochondria, dopaminergic auto-inhibition, mechanotransduction) are integrated, remain unresolved.\",\n      \"evidence\": \"No direct experimental resolution in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 13, 28]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 29, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 13, 28]}\n    ],\n    \"complexes\": [\n      \"Kv7.4/Kv7.5 heterotetramer\"\n    ],\n    \"partners\": [\n      \"KCNQ5\",\n      \"CALM1\",\n      \"KCNE4\",\n      \"HSP90AB1\",\n      \"CAV1\",\n      \"CNTNAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}