Affinage

KCNQ5

Potassium voltage-gated channel subfamily KQT member 5 · UniProt Q9NR82

Length
932 aa
Mass
102.2 kDa
Annotated
2026-06-10
51 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNQ5 (Kv7.5) is a voltage-gated potassium channel that activates slowly with depolarization to generate M-type currents controlling neuronal and smooth-muscle excitability (PMID:10816588, PMID:10787416, PMID:17071736). It assembles as homomers and as functional heteromers with multiple Kv7 partners—KCNQ3 (yielding larger, slower-activating currents) (PMID:10787416, PMID:10816588), KCNQ2 in an arrangement independent of KCNQ3 (PMID:35320039), and KCNQ4 and KCNQ1 in vascular smooth muscle, where alternating Kv7.4/Kv7.5 subunits in 2:2 stoichiometry reconstitute native M-currents (PMID:24558103, PMID:24855057, PMID:32903335). The auxiliary subunits KCNE1 and KCNE3 modulate KCNQ5 gating and direct it to specific membrane microdomains (PMID:19910673, PMID:22190306). In the nervous system the channel underlies medium and slow afterhyperpolarization currents in CA3 pyramidal neurons (PMID:20534576), localizes postsynaptically at inhibitory hippocampal synapses where it constrains interneuron excitability and supports fast network oscillations and spatial coding (PMID:25649132), and is targeted presynaptically to excitatory auditory-brainstem endings in an auditory-activity-dependent manner (PMID:17912742, PMID:20151361, PMID:25421809). In vascular and airway smooth muscle and interstitial cells of Cajal, KCNQ5 stabilizes the resting membrane potential, and its activity is bidirectionally controlled by phosphorylation: PKA phosphorylation of N-terminal Ser53 increases PIP2 affinity and enhances current, while PKC phosphorylation of C-terminal Ser441 lowers PIP2 affinity and suppresses current, allowing vasoconstrictors and bronchoconstrictors to inhibit the channel and PVAT-derived oxylipins to open it (PMID:17071736, PMID:24297175, PMID:26700561, PMID:28283479, PMID:30061510, PMID:31871302, PMID:38354270). De novo missense variants produce either gain-of-function (hyperpolarized activation, slowed deactivation, or markedly increased single-channel open probability) or loss-of-function (reduced current density with dominant-negative effects and, for R359C, altered PI(4,5)P2 binding), causing epilepsy, epileptic encephalopathy, and intellectual disability (PMID:28669405, PMID:35377796, PMID:35583973, PMID:36088682). KCNQ5 transcription is activated epigenetically through a GADD45A/TET1/R-loop axis that demethylates the KCNQ5 promoter in cortical excitatory neurons (PMID:41741708).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Established that KCNQ5 is a bona fide M-current channel, defining its core identity as a slowly activating, muscarinic-sensitive Kv7 subunit that heteromerizes with KCNQ3.

    Evidence Heterologous expression with voltage-clamp electrophysiology, linopirdine pharmacology, and muscarinic receptor co-expression in two independent labs

    PMID:10787416 PMID:10816588

    Open questions at the time
    • Native cell types expressing KCNQ5 not yet mapped
    • Heteromeric partners beyond KCNQ3 unexplored
  2. 2001 High

    Defined the pharmacological signature of KCNQ5/KCNQ3 channels, linking the recombinant channel to native M-currents through retigabine activation and linopirdine block.

    Evidence Stable CHO-cell expression with whole-cell voltage-clamp and quantitative drug profiling

    PMID:11159685

    Open questions at the time
    • Pharmacology of homomeric KCNQ5 vs heteromers not fully separated
    • Binding sites for drugs not mapped
  3. 2005 Medium

    Showed KCNQ5 is gated by physiological modulators (zinc, pH, cell volume), indicating sensitivity to the local chemical microenvironment.

    Evidence Xenopus oocyte two-electrode voltage-clamp with controlled Zn2+, pH, and tonicity

    PMID:15963599

    Open questions at the time
    • Molecular sites mediating Zn2+ and pH effects not identified
    • Physiological relevance in native cells untested
  4. 2006 High

    Identified KCNQ5 as the dominant Kv current setting resting potential in vascular smooth muscle and the target of vasoconstrictor (vasopressin/PKC) signaling.

    Evidence Patch-clamp, RNAi knockdown, PKC inhibition, and Ca2+ imaging in A7r5 aortic smooth muscle cells

    PMID:17071736

    Open questions at the time
    • Specific PKC phosphorylation site not yet mapped
    • Heteromeric partner composition in smooth muscle unresolved
  5. 2007 High

    Localized KCNQ5 to excitatory presynaptic terminals of the auditory brainstem, expanding its role beyond postsynaptic excitability control.

    Evidence High-resolution immunocytochemistry with synaptic markers plus cochlear ablation confirming presynaptic identity

    PMID:17912742

    Open questions at the time
    • Functional consequence of presynaptic KCNQ5 not directly measured
    • Mechanism of presynaptic targeting unknown
  6. 2009 Medium

    Defined the KCNE subunit selectivity of KCNQ5 and demonstrated that KCNQ5 alone sets smooth-muscle resting potential, refining its regulatory and physiological context.

    Evidence Two-electrode and whole-cell electrophysiology with Co-IP in oocytes/HEK/myoblasts (KCNE study) and shRNA knockdown with Ca2+ imaging in A7r5 cells

    PMID:19246091 PMID:19910673

    Open questions at the time
    • Structural basis of KCNE1/3 modulation unresolved
    • Single-lab findings for native co-expression
  7. 2010 High

    Established KCNQ5's in vivo role in afterhyperpolarization in a cell-type-specific manner and showed its synaptic localization depends on ongoing afferent activity.

    Evidence Dominant-negative Kcnq5(dn/dn) knock-in mice with CA3/CA1 patch-clamp; developmental immunocytochemistry with cochlear ablation; diclofenac mutagenesis study

    PMID:20151361 PMID:20534576 PMID:20876743

    Open questions at the time
    • Signal driving activity-dependent maintenance not identified
    • Determinants of differential diclofenac pharmacology incompletely defined
  8. 2011 Medium

    Extended KCNQ5's tissue distribution to retinal pigment epithelium and photoreceptors, implicating it in epithelial K+ absorption.

    Evidence Patch-clamp with XE991, RT-PCR, immunohistochemistry, and in situ hybridization in monkey retina

    PMID:21795522

    Open questions at the time
    • Functional contribution to K+ absorption not directly tested in vivo
    • Subunit partners in RPE unknown
  9. 2013 High

    Resolved the heteromeric architecture and trafficking of KCNQ5 in vascular smooth muscle and brain, and linked a KCNQ3/KCNQ5 variant to disease.

    Evidence Proximity ligation assay, siRNA, myography, dominant-negative and PKCα translocation systems; native-tissue Co-IP/IHC; oocyte co-expression of disease variant; ICC single-channel recordings; lipid-raft/FRAP analysis

    PMID:12890507 PMID:22190306 PMID:23596459 PMID:24297175 PMID:24375291 PMID:24558103

    Open questions at the time
    • Exact subunit stoichiometry not yet enforced
    • PKC phosphorylation site on Kv7.5 not yet mapped at this stage
  10. 2013 High

    Defined KCNQ5 as a postsynaptic calyx-neuron channel in the vestibular system contributing to vestibulo-ocular reflex function.

    Evidence Kcnq4-/-, Kcnq5(dn/dn), and double-mutant mice with hair-cell patch-clamp, VOR testing, and immunohistochemistry

    PMID:23408425

    Open questions at the time
    • Heteromeric composition in vestibular neurons not defined
    • Relative contributions in tonic vs phasic zones quantitatively incomplete
  11. 2014 High

    Established Kv7.1/Kv7.5 heteromers and their ER retention, and reported KCNQ5 association with CaM/VGluT1/GFAP in retina.

    Evidence Co-IP, FRET, FRAP, lipid-raft fractionation, and electrophysiology for Kv7.1/Kv7.5; in situ proximity ligation assay for retinal interactions

    PMID:24855057 PMID:25499209

    Open questions at the time
    • Direct biochemical confirmation of CaM binding lacking (PLA only)
    • Functional role of Kv7.1/Kv7.5 ER retention unresolved
  12. 2015 High

    Defined the dual phosphorylation logic of KCNQ5 and its role in inhibitory hippocampal circuits, linking subunit-specific PKA enhancement to network function.

    Evidence PLA-based phosphorylation assays with comparative subunit expression in A7r5 cells; immunofluorescence, slice/in vivo electrophysiology, and behavior in Kcnq5(dn/dn) mice

    PMID:25421809 PMID:25649132 PMID:26700561

    Open questions at the time
    • Phosphorylation residues not yet pinpointed at this stage
    • Causal link between synaptic localization and oscillation deficits indirect
  13. 2017 Medium

    Mapped the PKC phosphosite (Ser441) controlling bronchoconstrictor inhibition of KCNQ5 and established disease causation by de novo variants.

    Evidence S441A mutagenesis with PKCα knockdown and Ca2+ imaging in human airway smooth muscle; oocyte electrophysiology of four disease variants

    PMID:28283479 PMID:28669405

    Open questions at the time
    • Genotype-phenotype correlation across LOF/GOF variants incomplete
    • In vivo disease modeling not yet performed
  14. 2018 High

    Identified the N-terminal PKA phosphosite (Ser53) responsible for β-adrenergic enhancement, completing the bidirectional phosphorylation map.

    Evidence S53A/S53D mutagenesis with systematic exclusion of C-terminal sites and patch-clamp in human airway smooth muscle cells

    PMID:30061510

    Open questions at the time
    • Kinase anchoring/scaffold for site-specific phosphorylation unknown
  15. 2019 High

    Unified the phosphorylation findings mechanistically by showing PKA and PKC act through opposing changes in channel PIP2 affinity mapped to distinct N- and C-terminal domains.

    Evidence Chimeric channel domain swaps, site-directed mutagenesis, and Ci-VSP PIP2-depletion patch-clamp assays in A7r5 cells

    PMID:31871302

    Open questions at the time
    • Structural basis of PIP2-affinity changes not resolved
    • Quantitative coupling of phosphorylation to PIP2 binding incomplete
  16. 2020 Medium

    Determined the dominant native smooth-muscle channel configuration as a 2:2 alternating Kv7.4/Kv7.5 heterotetramer.

    Evidence Concatenated dimer/tetramer constructs with whole-cell patch-clamp and pharmacology in mesenteric artery myocytes

    PMID:32903335

    Open questions at the time
    • Stoichiometry inferred from concatemers may not reflect all native channels
    • Tissue-to-tissue variation in composition unaddressed
  17. 2022 High

    Resolved the distinct molecular mechanisms of gain- and loss-of-function disease variants and demonstrated KCNQ2/KCNQ5 heteromerization independent of KCNQ3.

    Evidence Single-channel noise analysis and biotinylation for G347 variants; systematic electrophysiology of 10 variants with CRISPR mouse EEG; split-intein tandems and native-brain mass spectrometry for KCNQ2/5

    PMID:35320039 PMID:35377796 PMID:35583973 PMID:36088682

    Open questions at the time
    • Structural mechanism of open-probability gain unresolved
    • Why some GoF alleles dominate heteromers and others do not is unclear
  18. 2023 High

    Established a physiological vasodilatory pathway in which PVAT-derived oxylipins open Kv7.5 to regulate arterial tone and blood pressure.

    Evidence Kcnq5-/- and Kcnq5(dn/dn) mice with wire myography, patch-clamp, lipidomics, RNA-Seq, and telemetry blood pressure

    PMID:38354270

    Open questions at the time
    • Direct binding site for oxylipins on Kv7.5 not identified
    • Coupling between oxylipin and channel gating unresolved
  19. 2024 Medium

    Demonstrated pharmacological rescue of dominant-negative KCNQ5 dysfunction, providing a therapeutic rationale for retigabine, gabapentin, and Zn2+.

    Evidence Whole-cell patch-clamp of R359C-expressing HEK cells and neurons with drug application

    PMID:38428481

    Open questions at the time
    • Efficacy not tested in vivo or in patient-derived neurons
    • Single-lab pharmacological rescue
  20. 2026 Medium

    Identified an epigenetic control mechanism for KCNQ5 transcription through a GADD45A/TET1/R-loop axis relevant to cortical excitability.

    Evidence Gadd45a knockout mice with in vivo electrophysiology, ChIP/methylation analysis, R-loop detection, and GADD45A–TET1 Co-IP

    PMID:41741708

    Open questions at the time
    • Independent replication pending
    • Whether this axis operates in other KCNQ5-expressing tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural basis for KCNQ5 gating, PIP2 coupling, drug binding, and disease-variant effects remains undefined.
  • No experimentally determined channel structure
  • Atomic-level mechanism of GoF open-probability increase unresolved
  • Structural site of oxylipin/zinc/drug action unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-397014 Muscle contraction 4 R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2
Partners
CALM1KCNE1KCNE3KCNQ1KCNQ2KCNQ3KCNQ4TET1
Complex memberships
Kv7.1/Kv7.5 heteromerKv7.2/Kv7.5 heteromerKv7.4/Kv7.5 heterotetramerKv7.5/Kv7.3 heteromer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 KCNQ5 encodes a voltage-gated potassium channel that activates slowly with depolarization, mediates M-type currents, forms heteromeric channels with KCNQ3, and is inhibited by M1 muscarinic receptor activation. A splice variant found in skeletal muscle displays altered gating kinetics. Heterologous expression, electrophysiology (voltage-clamp), pharmacology (linopirdine inhibition), muscarinic receptor co-expression The Journal of biological chemistry High 10787416 10816588
2000 KCNQ5 co-expressed with KCNQ3 forms functional heteromeric channels with 4-5-fold increased current amplitude, slower activation kinetics, and less inward rectification compared to KCNQ5 homomers. Xenopus oocyte expression, two-electrode voltage-clamp electrophysiology The Journal of biological chemistry High 10787416 10816588
2001 Heteromeric KCNQ5/KCNQ3 channels expressed in CHO cells are activated by retigabine (EC50 1.4 µM) via a leftward shift in voltage-dependence of activation, and inhibited by linopirdine (IC50 7.7 µM) and barium, with pharmacological properties similar to native M-currents. Stable expression in CHO cells, whole-cell voltage-clamp electrophysiology, pharmacological characterization British journal of pharmacology High 11159685
2003 KCNQ3 co-immunoprecipitates with both KCNQ2 and KCNQ5 in human temporal neocortex and hippocampus, but no association was detected between KCNQ2 and KCNQ5. KCNQ5 is expressed in pyramidal and non-pyramidal neurons and glial cells in these regions. Co-immunoprecipitation from human brain tissue, immunocytochemistry Neuroscience Medium 12890507
2005 Mouse KCNQ5 channels are modulated by extracellular zinc (pH-dependent potentiation, EC50 21.8 µM at pH 7.4), inhibited by extracellular acidification (pKa 6.1), and regulated by small changes in cell volume (osmotic stress). Channels are activated by retigabine (EC50 2.0 µM) and inhibited by linopirdine and XE-991. Xenopus oocyte expression, two-electrode voltage-clamp, pharmacological manipulation of Zn2+, pH, and tonicity Brain research. Molecular brain research Medium 15963599
2006 In A7r5 rat aortic smooth muscle cells, KCNQ5 mediates the predominant Kv current; vasopressin (AVP, 100 pM) inhibits this current via PKC-dependent phosphorylation, leading to membrane depolarization and action potential/Ca2+ spike generation. KCNQ5 knockdown by RNAi reduced the Kv current and induced spontaneous action potentials. Patch-clamp electrophysiology, RNAi knockdown, pharmacological PKC inhibition (calphostin C), RT-PCR, Ca2+ imaging American journal of physiology. Heart and circulatory physiology High 17071736
2007 KCNQ5 is localized predominantly in excitatory (glutamatergic) presynaptic endings and dendrites of auditory brainstem nuclei (cochlear nucleus, superior olivary complex, lateral lemniscus, inferior colliculus). KCNQ5 immunoreactivity in the cochlear nucleus disappeared after cochlea removal, confirming presynaptic localization in auditory nerve endings. KCNQ5 was absent from glycinergic and GABAergic endings. High-resolution immunocytochemistry, double labeling with synaptic markers (synaptophysin, syntaxin), co-localization with MAP2, cochlear ablation experiment The Journal of comparative neurology High 17912742
2009 KCNE1 slows KCNQ5 activation kinetics and suppresses inward rectification, while KCNE3 drastically inhibits KCNQ5 currents; neither KCNE2, KCNE4, nor KCNE5 significantly affected KCNQ5. These regulatory associations occur in skeletal muscle myoblasts where both Kv7.5 and KCNE subunits are natively co-expressed. Two-electrode voltage-clamp in Xenopus oocytes, whole-cell patch-clamp in HEK-293 cells, co-immunoprecipitation, RT-PCR in myoblasts Cellular physiology and biochemistry Medium 19910673
2009 KCNQ5 channel suppression alone (by shRNA knockdown) is sufficient to depolarize the resting membrane potential and trigger spontaneous action potential firing and Ca2+ spiking in A7r5 smooth muscle cells, demonstrating KCNQ5 as the primary stabilizer of resting membrane potential in these cells. shRNA knockdown of KCNQ5, patch-clamp electrophysiology, fura-2 Ca2+ imaging Cell calcium Medium 19246091
2010 KCNQ5 channels contribute to both the medium and slow afterhyperpolarization (AHP) currents in CA3 hippocampal neurons in a cell-type specific manner. In Kcnq5(dn/dn) mice carrying a dominant-negative pore mutation that renders KCNQ5-containing homo- and heteromeric channels nonfunctional, AHP currents are significantly reduced in CA3 (high KCNQ5 expression) but not CA1 (low KCNQ5 expression) pyramidal neurons. Dominant-negative knock-in mouse model, whole-cell patch-clamp electrophysiology, immunohistochemistry for KCNQ2/3 localization Proceedings of the National Academy of Sciences of the United States of America High 20534576
2010 KCNQ5 targeting to synaptic endings in auditory brainstem neurons occurs around the time of hearing onset (postnatal day 12-13) independent of auditory nerve activity, but long-term maintenance of this synaptic localization requires ongoing peripheral auditory input. Immunocytochemistry during postnatal development, cochlear ablation at various postnatal ages, qRT-PCR for KCNQ5 transcript levels The Journal of comparative neurology Medium 20151361
2010 Diclofenac inhibits KCNQ5 homomeric channels (reducing maximum conductance by 53%) but activates KCNQ4 homomeric channels (+38%). Mutation of a basic residue (lysine) in the KCNQ5 voltage-sensing domain to glycine (the residue in KCNQ4) resulted in more effective block rather than activation, indicating the differential pharmacology is not determined by this residue alone. Native A7r5 cells express only KCNQ5 channels and their diclofenac responses match overexpressed KCNQ5; mesenteric artery myocytes express predominantly KCNQ4/5 heteromers. Patch-clamp electrophysiology in A7r5 cells and mesenteric artery myocytes, heterologous overexpression of KCNQ4, KCNQ5, and KCNQ4/5, site-directed mutagenesis Molecular pharmacology High 20876743
2011 KCNQ5 is expressed at the basal membrane of retinal pigment epithelium (RPE) cells and contributes to the M-type K+ current (eliminated by XE991) of RPE, suggesting a role in active K+ absorption. KCNQ5 is also present in cone and rod photoreceptor inner segments and plexiform layers of the neural retina. Patch-clamp electrophysiology with XE991 blocker, RT-PCR, immunohistochemistry, in situ hybridization in monkey retina American journal of physiology. Cell physiology Medium 21795522
2012 KCNQ5 forms oligomeric channels specifically with KCNE1 and KCNE3 (not other KCNEs), and targets to cholesterol-poor (non-lipid raft) membrane microdomains. KCNQ5 association impairs KCNE3 localization to lipid raft microdomains, contributing to spatial regulation of KCNE3. Co-immunoprecipitation, confocal microscopy, lipid raft isolation, fluorescence recovery after photobleaching (FRAP) in HEK293 cells Muscle & nerve Medium 22190306
2013 Kv7.4 and Kv7.5 proteins form predominantly functional heterotetramers in vascular smooth muscle cells (VSMCs) of middle cerebral arteries. Proximity ligation assay confirmed Kv7.4/Kv7.5 heteromers. siRNA against KCNQ5 reduced myogenic constriction in response to intravascular pressure increases but did not affect CGRP-induced vasodilation, while KCNQ4 siRNA reduced both responses. Proximity ligation assay, siRNA knockdown, isometric tension recordings, isobaric myography Arteriosclerosis, thrombosis, and vascular biology High 24558103
2013 Kv7.4/Kv7.5 heteromers are endogenously expressed in vascular smooth muscle cells as shown by proximity ligation assay. PKCα activation suppresses endogenous Kv7 currents in vascular smooth muscle. Vasopressin (100-500 pM) and phorbol ester each inhibit Kv7.5 and Kv7.4/7.5 (but not Kv7.4 alone) channels via PKC-dependent phosphorylation of Kv7.5 subunits. Proximity ligation assay, dominant-negative subunit expression, inducible PKCα translocation system, patch-clamp electrophysiology, PKC phosphorylation assay The Journal of biological chemistry High 24297175
2013 KV7.3 p.P574S variant significantly reduced potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes, but not with KV7.2 or KV7.4, demonstrating that heteromeric KV7.3/KV7.5 channel dysfunction is associated with autism spectrum disorder pathogenesis. The variant did not affect trafficking of KV7.3/5 heteromers. Xenopus oocyte electrophysiology, heterologous co-expression, immunocytochemistry for trafficking in HEK293 cells and rat hippocampal neurons Frontiers in genetics Medium 23596459
2013 KCNQ5 mediates XE991-sensitive, cholinergically-regulated Kv7 currents (single channel conductance 3.4 pS) in intramuscular interstitial cells of Cajal (ICC-IM) of mouse colon, but not in myenteric plexus ICC (ICC-MP). Muscarinic stimulation with carbachol inhibited this channel activity. Cell-attached patch-clamp, single cell RT-PCR, double immunohistochemistry (c-Kit/KV7.5), pharmacological blockade with XE991 Pflugers Archiv : European journal of physiology Medium 24375291
2013 KCNQ4 and KCNQ5 are expressed in postsynaptic calyx-forming neurons of the vestibular system (not in hair cells), as demonstrated unambiguously using Kcnq4(-/-), Kcnq5(dn/dn), and double mutant mice. Kcnq4(-/-)/Kcnq5(dn/dn) double mutant mice display altered vestibulo-ocular reflexes, with KCNQ4 having greater impact due to preferential expression in phasic (central zone) neurons versus KCNQ5 in tonic (peripheral zone) neurons. Genetic mouse models (knockout and dominant-negative knock-in), whole-cell patch-clamp of vestibular hair cells, vestibulo-ocular reflex testing, immunohistochemistry The Journal of biological chemistry High 23408425
2014 KCNQ5 channels interact physically with calmodulin (CaM), vesicular glutamate transporter 1 (VGluT1), and GFAP in rat retina, as demonstrated by in situ proximity ligation assay. The KCNQ5/CaM interaction changes with retinal degeneration progression, suggesting KCNQ5 activity may be moderated by calmodulin. In situ proximity ligation assay, immunocytochemistry, Western blot, calcium recording Experimental eye research Low 25499209
2014 Kv7.1 and Kv7.5 form functional heterotetrameric channels in vascular smooth muscle. These heteromers are preferentially retained at the endoplasmic reticulum. Predominant presence of Kv7.5 promotes release of Kv7.1/Kv7.5 oligomers from lipid raft microdomains. KCNE1 and KCNE3 further modulate Kv7.1/Kv7.5 heteromer function. Co-immunoprecipitation, FRET, FRAP, electrophysiology in oocytes and mammalian cells, lipid raft fractionation Arteriosclerosis, thrombosis, and vascular biology High 24855057
2014 Auditory activity from peripheral afferents is necessary to maintain synaptic localization of KCNQ5 in excitatory endings (endbulbs and calyces of Held) of auditory brainstem neurons. After cochlear ablation or intracochlear TTX injection, KCNQ5 immunoreactivity disappeared from synaptic endings and redistributed to cell bodies. Cochlear ablation, intracochlear tetrodotoxin injection, immunocytochemistry, Western blot, qRT-PCR Journal of neuroscience research Medium 25421809
2015 KCNQ5 localizes to postsynaptic sites of inhibitory synapses on hippocampal pyramidal cells and in interneurons. Loss of KCNQ5 function (Kcnq5(dn/dn) mice) increases interneuron excitability, enhances phasic and tonic inhibition, decreases electrical shunting of inhibitory postsynaptic currents, and in vivo reduces fast hippocampal oscillations (gamma and ripple) and impairs spatial representations. Immunofluorescence localization, whole-cell patch-clamp in acute slices, in vivo electrophysiology (LFP, single-unit recording), spatial navigation assessment in Kcnq5(dn/dn) mice Nature communications High 25649132
2015 PKA-dependent enhancement of smooth muscle Kv7 currents primarily targets Kv7.5 subunits. β-adrenergic receptor activation via isoproterenol induces PKA-dependent phosphorylation of Kv7.5 (but not Kv7.4) subunits, producing 2-4-fold enhancement of Kv7.5 homomeric currents. Heteromeric Kv7.4/7.5 channels show modest enhancement; Kv7.4 homomers are insensitive. Patch-clamp electrophysiology, exogenous expression of homomeric and heteromeric channels in A7r5 cells, proximity ligation assay for phosphorylation, pharmacological PKA activation/inhibition Molecular pharmacology High 26700561
2017 De novo heterozygous missense mutations in KCNQ5 cause shifts in voltage dependence of activation and altered activation/deactivation kinetics, with both loss-of-function and gain-of-function variants leading to intellectual disability and epileptic encephalopathy. Xenopus oocyte electrophysiology of four disease variants, biophysical analysis of V50 shifts and kinetics American journal of human genetics Medium 28669405
2017 PKCα mediates histamine-induced inhibition of Kv7.5 in human airway smooth muscle cells. Histamine suppresses Kv7.5 currents via PKC-dependent phosphorylation at serine 441 on Kv7.5; S441A mutation abolishes the inhibitory effect of histamine. This inhibition is associated with membrane depolarization and Ca2+ influx via L-type voltage-sensitive Ca2+ channels. Whole-cell patch-clamp, PKCα knockdown and inhibition, site-directed mutagenesis (S441A), PKC phosphorylation assay, Ca2+ imaging with verapamil American journal of physiology. Lung cellular and molecular physiology High 28283479
2018 PKA-dependent enhancement of Kv7.5 channel activity in airway smooth muscle cells requires phosphorylation of serine 53 on the amino terminus of Kv7.5. S53A mutation significantly reduced current enhancement by β-adrenergic receptor activation or cAMP elevation; S53D phosphomimic exhibited constitutive activation. Mutations at 6 C-terminal putative PKA sites had no effect. Site-directed mutagenesis (S53A, S53D, 6 C-terminal S/T to A mutations), whole-cell patch-clamp in human airway smooth muscle cells, pharmacological PKA activation International journal of molecular sciences High 30061510
2019 PKA-dependent phosphorylation of S53 on the Kv7.5 amino terminus increases PIP2 affinity of the channel, thereby enhancing channel activity. PKC-dependent phosphorylation of the Kv7.5 carboxy-terminus reduces PIP2 affinity, suppressing channel activity. Chimeric channel experiments mapped these functional domains: the Kv7.5 N-terminus confers PKA/cAMP responsiveness while the Kv7.5 C-terminus confers PKC-dependent inhibitory responsiveness. Chimeric channel construction, site-directed mutagenesis, patch-clamp electrophysiology with Ci-VSP PIP2 depletion assay, pharmacological activation of PKA and PKC in A7r5 cells Molecular pharmacology High 31871302
2020 Heteromeric KCNQ5/KCNQ4 channels with alternating Kv7.4 and Kv7.5 subunits in a 2:2 stoichiometry (constructed as concatenated tetramers) reproduced the biophysical, regulatory, and pharmacological characteristics of native smooth muscle M-currents in mesenteric artery myocytes, identifying this as the likely dominant configuration. Concatenated dimer/tetramer constructs expressed in smooth muscle cells, whole-cell patch-clamp electrophysiology, pharmacological characterization Frontiers in physiology Medium 32903335
2022 KCNQ5 pore variants G347S and G347A cause gain-of-function through a large increase in single-channel open probability (>10-fold increase in maximal current density, voltage-independent current component, slower deactivation, hyperpolarized activation), without changes in membrane abundance or single-channel conductance. This GoF mechanism is insensitive to PIP2 manipulation. Whole-cell and single-channel electrophysiology, non-stationary noise analysis, biotinylation surface expression assay, PIP2 manipulation, mutagenesis in HEK cells Proceedings of the National Academy of Sciences of the United States of America High 35377796
2022 KCNQ2 and KCNQ5 form functional heteromeric channels independent of KCNQ3. Using split-intein protein trans-splicing to form obligate KCNQ2/5 tandems, channels formed functionally in the absence of KCNQ3. Mass spectrometry confirmed native KCNQ2-KCNQ5 association in mouse brain even in KCNQ3-null animals. KCNQ2/3/5 trimeric heteromers are also consistent with expression data. Split-intein protein trans-splicing (tandem constructs), heterologous expression electrophysiology, mass spectrometry of native brain channels from KCNQ3-null mice Proceedings of the National Academy of Sciences of the United States of America High 35320039
2022 All eight KCNQ5 missense variants causing epilepsy/intellectual disability produced gain-of-function (hyperpolarized V50 of activation or slowed deactivation kinetics); two nonsense variants produced loss-of-function. One severe GoF allele (P369T) extended dominant GoF effects to heteromeric KCNQ5/3 channels. CRISPR/Cas9 Kcnq5 loss-of-function mouse lines exhibit handling- and thermal-induced seizures with abnormal cortical EEGs. Whole-cell electrophysiology in HEK293/CHO cells, CRISPR/Cas9 knockout mouse generation, EEG recording Journal of neurophysiology High 35583973
2022 Loss-of-function KCNQ5 missense variants reduce current density without affecting surface expression (confirmed by biotinylation assay). Three variants exert dominant-negative effects on co-expressed wild-type Kv7.5 and Kv7.5/Kv7.3 channels. The R359C variant specifically alters PI(4,5)P2 interaction (phospholipid overlay assay). Whole-cell patch-clamp in mammalian cells, surface biotinylation assay, phospholipid overlay assay, homology modelling, co-expression with WT channels EBioMedicine High 36088682
2023 PVAT (perivascular adipose tissue) causes hyperpolarization and relaxation of small arteries via activation of smooth muscle Kv7.5 channels. Oxylipins released by PVAT potentiate vasodilation by opening Kv7.5 channels. Kcnq5 knockout/dominant-negative mice show impaired PVAT-mediated vasodilation and altered blood pressure. Genetic mouse models (Kcnq5-/-, Kcnq5(dn/dn), double mutants), wire myography, patch-clamp, sharp-electrode membrane potential recording, targeted lipidomics for oxylipins, RNA-Seq, telemetry blood pressure Hypertension High 38354270
2024 Retigabine and gabapentin restore M-current amplitudes in HEK cells expressing dominant-negative R359C KCNQ5 (homomeric or heteromeric channels with WT Kv7.5 or Kv7.3). Overexpression of WT Kv7.5 inhibits neuronal firing by increasing M-current; R359C overexpression has the opposite effect and decreases medium AHP current. Both drugs and Zn2+ reduce neuronal firing to near-normal levels. Whole-cell patch-clamp in HEK cells and neurons, pharmacological application of retigabine, gabapentin, and ZnCl2 to R359C-expressing cells Neuropharmacology Medium 38428481
2026 GADD45A recruits TET1 to the CpG islands of the KCNQ5 promoter via recognition of R-loop structures (formed with a nearby antisense lncRNA), enabling DNA demethylation and transcriptional activation of KCNQ5 in cortical excitatory neurons. In Gadd45a knockout mice, TET1 fails to be recruited to the KCNQ5 promoter, reducing KCNQ5 expression and causing abnormal neuronal firing in the prefrontal cortex and autism-like phenotypes. Gadd45a knockout mice, in vivo electrophysiology, ChIP/methylation analysis of KCNQ5 promoter, identification of R-loop structures, TET1 co-immunoprecipitation with GADD45A Molecular psychiatry Medium 41741708

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. The Journal of biological chemistry 327 10816588
2000 Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. The Journal of biological chemistry 228 10787416
2010 The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus. Proceedings of the National Academy of Sciences of the United States of America 107 20534576
2017 Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy. American journal of human genetics 86 28669405
2014 Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity. Arteriosclerosis, thrombosis, and vascular biology 81 24558103
2001 Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. British journal of pharmacology 81 11159685
2013 Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. The Journal of biological chemistry 62 24297175
2006 Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells. American journal of physiology. Heart and circulatory physiology 62 17071736
2003 Localization of KCNQ5 in the normal and epileptic human temporal neocortex and hippocampal formation. Neuroscience 57 12890507
2015 Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents. Molecular pharmacology 55 26700561
2015 KCNQ5 K(+) channels control hippocampal synaptic inhibition and fast network oscillations. Nature communications 54 25649132
2005 The KCNQ5 potassium channel from mouse: a broadly expressed M-current like potassium channel modulated by zinc, pH, and volume changes. Brain research. Molecular brain research 53 15963599
2010 Diclofenac distinguishes among homomeric and heteromeric potassium channels composed of KCNQ4 and KCNQ5 subunits. Molecular pharmacology 52 20876743
2013 Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders. Frontiers in genetics 43 23596459
2007 The potassium channel KCNQ5/Kv7.5 is localized in synaptic endings of auditory brainstem nuclei of the rat. The Journal of comparative neurology 41 17912742
2013 Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models. The Journal of biological chemistry 38 23408425
2012 Kv7.5 is the primary Kv7 subunit expressed in C-fibers. The Journal of comparative neurology 35 22134895
2018 Down-expression of P2RX2, KCNQ5, ERBB3 and SOCS3 through DNA hypermethylation in elderly women with presbycusis. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 34 29325454
2022 Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy. Proceedings of the National Academy of Sciences of the United States of America 32 35377796
2011 KCNQ5/K(v)7.5 potassium channel expression and subcellular localization in primate retinal pigment epithelium and neural retina. American journal of physiology. Cell physiology 31 21795522
2022 KCNQ2 and KCNQ5 form heteromeric channels independent of KCNQ3. Proceedings of the National Academy of Sciences of the United States of America 29 35320039
2009 Opposite regulation of KCNQ5 and TRPC6 channels contributes to vasopressin-stimulated calcium spiking responses in A7r5 vascular smooth muscle cells. Cell calcium 29 19246091
2009 Functional implications of KCNE subunit expression for the Kv7.5 (KCNQ5) channel. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 27 19910673
2014 Functional assembly of Kv7.1/Kv7.5 channels with emerging properties on vascular muscle physiology. Arteriosclerosis, thrombosis, and vascular biology 26 24855057
2021 KCNQ5 and C9orf50 Methylation in Stool DNA for Early Detection of Colorectal Cancer. Frontiers in oncology 22 33585248
2010 KCNQ5 reaches synaptic endings in the auditory brainstem at hearing onset and targeting maintenance is activity-dependent. The Journal of comparative neurology 21 20151361
2014 Relationship between rat retinal degeneration and potassium channel KCNQ5 expression. Experimental eye research 20 25499209
2017 Genetic Association Study of KCNQ5 Polymorphisms with High Myopia. BioMed research international 19 28884119
2018 Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells. International journal of molecular sciences 18 30061510
2012 CTCF mediates the cell-type specific spatial organization of the Kcnq5 locus and the local gene regulation. PloS one 17 22347474
2022 Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability. Journal of neurophysiology 16 35583973
2017 PKC-dependent regulation of Kv7.5 channels by the bronchoconstrictor histamine in human airway smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology 16 28283479
2018 Intragenic duplication of KCNQ5 gene results in aberrant splicing leading to a premature termination codon in a patient with intellectual disability. European journal of medical genetics 15 30359776
2000 The new voltage gated potassium channel KCNQ5 and neonatal convulsions. Neuroreport 15 10884071
2022 Circ_KCNQ5 participates in the progression of childhood acute myeloid leukemia by enhancing the expression of RAB10 via binding to miR-622. Hematology (Amsterdam, Netherlands) 13 35413218
2022 Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies. EBioMedicine 12 36088682
2021 The Changes of KCNQ5 Expression and Potassium Microenvironment in the Retina of Myopic Guinea Pigs. Frontiers in physiology 9 35002772
2023 KCNQ5 Controls Perivascular Adipose Tissue-Mediated Vasodilation. Hypertension (Dallas, Tex. : 1979) 8 38354270
2020 Changes in expression of Kv7.5 and Kv7.2 channels in dorsal root ganglion neurons in the streptozotocin rat model of painful diabetic neuropathy. Neuroscience letters 8 32739272
2020 Remodeling of Kv7.1 and Kv7.5 Expression in Vascular Tumors. International journal of molecular sciences 7 32825637
2014 Serum starvation-induced voltage-gated potassium channel Kv7.5 expression and its regulation by Sp1 in canine osteosarcoma cells. International journal of molecular sciences 7 24434641
2013 Cholinergic signalling-regulated KV7.5 currents are expressed in colonic ICC-IM but not ICC-MP. Pflugers Archiv : European journal of physiology 7 24375291
2012 Targeting of Kv7.5 (KCNQ5)/KCNE channels to surface microdomains of cell membranes. Muscle & nerve 7 22190306
2017 Downregulation of KCNQ5 expression in the rat pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia. Journal of pediatric surgery 6 28189443
2020 Heteromeric Channels Formed From Alternating Kv7.4 and Kv7.5 α-Subunits Display Biophysical, Regulatory, and Pharmacological Characteristics of Smooth Muscle M-Currents. Frontiers in physiology 5 32903335
2019 Structural Determinants of Kv7.5 Potassium Channels That Confer Changes in Phosphatidylinositol 4,5-Bisphosphate (PIP2) Affinity and Signaling Sensitivities in Smooth Muscle Cells. Molecular pharmacology 5 31871302
2016 Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia. CNS & neurological disorders drug targets 3 26553166
2014 Loss of auditory activity modifies the location of potassium channel KCNQ5 in auditory brainstem neurons. Journal of neuroscience research 3 25421809
2025 Early Diagnosis of Colorectal Cancer via Plasma-Derived SDC2, KCNQ5, and IKZF1 Methylation Levels. Clinical laboratory 1 40066557
2024 Retigabine and gabapentin restore channel function and neuronal firing in a cellular model of an epilepsy-associated dominant-negative KCNQ5 variant. Neuropharmacology 1 38428481
2026 The novel role of GADD45A in the etiology of autism: modulating neuronal excitability via TET1/R-loop dependent regulation of KCNQ5. Molecular psychiatry 0 41741708

Missed literature

Know a paper Affinage missed for KCNQ5? Flag it for the maintainers and the community.

No submissions yet.