Affinage

KCNQ5

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

Length
932 aa
Mass
102.2 kDa
Annotated
2026-04-28
51 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNQ5 (Kv7.5) is a voltage-gated potassium channel subunit that generates slowly activating, non-inactivating M-type currents to regulate neuronal excitability, vascular smooth muscle tone, and network oscillations across the brain, vasculature, and visceral organs. It assembles as homomers or as heterotetramers with KCNQ3, KCNQ2, KCNQ4, or KCNQ1 subunits and is modulated by accessory KCNE1/KCNE3 subunits; channel activity is bidirectionally controlled by PKC-dependent phosphorylation of S441 (inhibitory, reducing PIP2 affinity) and PKA-dependent phosphorylation of S53 (stimulatory, increasing PIP2 affinity), linking it to muscarinic and β-adrenergic signaling cascades (PMID:10816588, PMID:28283479, PMID:30061510, PMID:31871302). In the hippocampus, KCNQ5 localizes postsynaptically at inhibitory synapses where it controls interneuron excitability, gamma/ripple oscillations, and spatial representations; in auditory brainstem it targets excitatory synaptic terminals in an activity-dependent manner (PMID:25649132, PMID:17912742, PMID:20151361). De novo missense mutations in KCNQ5 cause intellectual disability and epileptic encephalopathy through both gain-of-function and loss-of-function mechanisms, and loss-of-function variants with dominant-negative effects underlie genetic generalized epilepsy (PMID:28669405, PMID:35377796, PMID:36088682).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Identification of KCNQ5 as a functional M-current channel resolved whether additional KCNQ family members contributed to neuronal M-currents beyond KCNQ2/3, establishing that KCNQ5 produces slowly activating, muscarinic-sensitive currents as homomers and KCNQ3 heteromers.

    Evidence Heterologous expression in Xenopus oocytes and mammalian cells with voltage clamp and M1 receptor co-expression

    PMID:10787416 PMID:10816588

    Open questions at the time
    • Endogenous heteromer stoichiometry in neurons not yet defined
    • In vivo physiological role not established
  2. 2003 Medium

    Demonstration that KCNQ5 co-immunoprecipitates with KCNQ3 but not KCNQ2 in human brain established the endogenous heteromeric partner selectivity of KCNQ5 in native tissue.

    Evidence Co-immunoprecipitation from human temporal neocortex and hippocampus with subunit-specific antisera

    PMID:12890507

    Open questions at the time
    • KCNQ2/KCNQ5 direct association was later discovered, suggesting technical limitations of this early co-IP
    • Stoichiometry of native complexes unknown
  3. 2006 High

    Knockdown studies in vascular smooth muscle cells established that KCNQ5 is a critical determinant of resting membrane potential and that its suppression by vasopressin via PKC causes depolarization, action potentials, and Ca²⁺ spiking — linking KCNQ5 to vasoconstriction signaling.

    Evidence shRNA knockdown, patch clamp, fura-2 Ca²⁺ imaging, PKC pharmacology in A7r5 cells

    PMID:17071736 PMID:19246091

    Open questions at the time
    • Specific PKC phosphorylation site on KCNQ5 not yet identified
    • In vivo vascular relevance not demonstrated
  4. 2007 High

    Localization of KCNQ5 to excitatory synaptic terminals in auditory brainstem, with activity-dependent developmental redistribution from soma to synapse at hearing onset, revealed a presynaptic role and an experience-dependent targeting mechanism.

    Evidence Immunocytochemistry with synaptic markers, developmental time course, cochlear ablation in rodents

    PMID:17912742 PMID:20151361

    Open questions at the time
    • Molecular mechanism of activity-dependent synaptic targeting unknown
    • Functional consequence at the synapse not directly measured
  5. 2009 High

    Systematic screening of KCNE accessory subunits revealed that KCNE1 enhances and KCNE3 drastically inhibits KCNQ5 currents, defining the accessory subunit repertoire that tunes KCNQ5 channel properties.

    Evidence Co-expression in oocytes and HEK-293 cells with full electrophysiological characterization

    PMID:19910673

    Open questions at the time
    • Physiological tissues where KCNE1/KCNE3 regulate KCNQ5 in vivo not identified
    • Structural basis of KCNE selectivity unknown
  6. 2010 High

    A dominant-negative knock-in mouse model demonstrated that KCNQ5 is required for medium and slow afterhyperpolarization currents specifically in CA3 hippocampal neurons, establishing its cell-type-specific contribution to neuronal excitability in vivo.

    Evidence Kcnq5dn/dn mice, whole-cell patch clamp in hippocampal slices, immunohistochemistry

    PMID:20534576

    Open questions at the time
    • Behavioral consequences of CA3 hyperexcitability not tested
    • Whether KCNQ5 acts as homomer or heteromer in CA3 not resolved
  7. 2013 High

    Multiple studies converged to show that KCNQ4/KCNQ5 heterotetramers are the predominant functional channels in cerebral and mesenteric artery smooth muscle, mediating myogenic constriction, and that PKC selectively phosphorylates KCNQ5 (not KCNQ4) within these heteromers to suppress current.

    Evidence Proximity ligation assay, siRNA, isobaric myography in rat cerebral artery; inducible PKCα translocation, phosphorylation assays in mesenteric artery myocytes

    PMID:24297175 PMID:24558103

    Open questions at the time
    • Specific PKC phosphorylation site not yet mapped
    • Subunit arrangement within heterotetramer not determined
  8. 2015 High

    Immunoelectron microscopy and in vivo recordings in Kcnq5dn/dn mice revealed that KCNQ5 localizes postsynaptically at hippocampal inhibitory synapses, where it controls interneuron excitability, tonic/phasic inhibition, and gamma/ripple oscillations critical for spatial coding.

    Evidence Immunoelectron microscopy, hippocampal slice electrophysiology, in vivo place cell recordings in Kcnq5dn/dn mice

    PMID:25649132

    Open questions at the time
    • Behavioral consequences for spatial memory not directly assessed
    • Molecular basis for selective inhibitory synapse targeting unknown
  9. 2017 High

    Identification of PKC-dependent S441 phosphorylation as the inhibitory site and subsequently PKA-dependent S53 phosphorylation as the stimulatory site resolved the bidirectional kinase regulation of KCNQ5, showing that PKA acts by increasing PIP2 affinity via the N-terminus while PKC decreases PIP2 affinity via the C-terminus.

    Evidence Site-directed mutagenesis of S441 and S53, chimeric Kv7.4/7.5 domain swaps, Ci-VSP PIP2 depletion, patch clamp in human airway smooth muscle cells

    PMID:28283479 PMID:30061510 PMID:31871302

    Open questions at the time
    • Structural basis for how S53 phosphorylation allosterically enhances PIP2 binding unknown
    • Whether these phosphorylation sites are regulated identically in neurons and smooth muscle not tested
  10. 2017 High

    De novo KCNQ5 missense mutations were identified as a cause of intellectual disability and epileptic encephalopathy, with functional characterization revealing both gain-of-function and loss-of-function mechanisms converging on pathological neuronal excitability.

    Evidence Exome sequencing in affected families, biophysical characterization of variants in Xenopus oocytes and HEK cells

    PMID:28669405

    Open questions at the time
    • Genotype-phenotype correlations across GOF vs LOF mechanisms not fully delineated
    • No mouse model yet recapitulating specific patient variants
  11. 2022 High

    Mass spectrometry of native brain channels and constrained tandem constructs demonstrated that KCNQ2/KCNQ5 heteromers exist endogenously independent of KCNQ3, expanding the combinatorial repertoire of neuronal M-channels and overturning the earlier finding that KCNQ2 and KCNQ5 do not associate.

    Evidence Split-intein protein trans-splicing, heterologous patch clamp, mass spectrometry of native brain complexes

    PMID:35320039

    Open questions at the time
    • Physiological contexts where KCNQ2/5 heteromers predominate over KCNQ2/3 or KCNQ3/5 not defined
    • Functional differences between KCNQ2/5 and KCNQ2/3/5 trimeric heteromers unclear
  12. 2022 High

    Comprehensive functional analysis of disease-associated KCNQ5 variants established that most missense variants cause gain-of-function (via increased open probability or hyperpolarized activation) while nonsense and some missense variants exert dominant-negative loss-of-function, with the R359C variant specifically disrupting PIP2 interaction.

    Evidence Nonstationary noise analysis, biotinylation surface expression, phospholipid overlay assay, CRISPR mouse EEG in multiple independent studies

    PMID:35377796 PMID:35583973 PMID:36088682

    Open questions at the time
    • Whether GOF and LOF variants require distinct therapeutic strategies not proven in vivo
    • Structural basis for gain-of-function at G347 position awaits cryo-EM
  13. 2023 High

    Genetic mouse models demonstrated that perivascular adipose tissue-derived oxylipins activate KCNQ5 in resistance artery smooth muscle to cause hyperpolarization and vasorelaxation, establishing KCNQ5 as a blood pressure regulator in vivo.

    Evidence Wire myography, patch clamp, telemetry blood pressure, targeted lipidomics in Kcnq5−/− and Kcnq5dn/dn mice

    PMID:38354270

    Open questions at the time
    • Identity of the specific oxylipin species and their receptor/mechanism of KCNQ5 activation not fully resolved
    • Relevance to human blood pressure regulation not confirmed
  14. 2026 Medium

    Discovery that GADD45A recruits TET1 to R-loop structures at the KCNQ5 promoter for DNA demethylation revealed the first epigenetic mechanism controlling KCNQ5 transcription, linking promoter methylation status to M-current amplitude and neuronal firing.

    Evidence Gadd45a knockout mice, ChIP/TET1 recruitment assays, R-loop analysis, promoter methylation profiling in cortical neurons

    PMID:41741708

    Open questions at the time
    • Whether KCNQ5 promoter demethylation is dynamically regulated by neuronal activity is unknown
    • Independent replication and relevance beyond cortical excitatory neurons not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of KCNQ5 homo- and heteromeric channels, the molecular basis for subtype-specific subcellular targeting (inhibitory synapse vs presynaptic terminal), and whether gain-of-function and loss-of-function epilepsy variants require distinct therapeutic approaches in vivo.
  • No cryo-EM or X-ray structure of KCNQ5-containing channels
  • Mechanism of selective targeting to inhibitory postsynaptic sites unknown
  • Therapeutic strategy for GOF vs LOF disease variants not validated in animal models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 7 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4
Partners
KCNE1KCNE3KCNQ1KCNQ2KCNQ3KCNQ4
Complex memberships
Kv7.1/Kv7.5 heterotetramerKv7.2/Kv7.5 heterotetramerKv7.3/Kv7.5 heterotetramerKv7.4/Kv7.5 heterotetramer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 KCNQ5 forms functional homomeric channels that activate slowly with depolarization and produce M-type currents; it also forms heteromeric channels with KCNQ3, displaying altered voltage dependence and pharmacology. A splice variant found in skeletal muscle displays altered gating kinetics. Heterologous expression in Xenopus oocytes and mammalian cells, whole-cell voltage clamp, pharmacological profiling (linopirdine, TEA), M1 muscarinic receptor co-activation The Journal of biological chemistry High 10787416 10816588
2000 KCNQ5 is inhibited by M1 muscarinic receptor activation, placing it in the muscarinic/M-current signaling pathway in neurons. Co-expression of M1 receptor with KCNQ5 in heterologous cells, whole-cell patch clamp The Journal of biological chemistry High 10816588
2001 Heteromeric KCNQ5/KCNQ3 channels stably expressed in CHO cells are activated by retigabine (EC50 1.4 µM) via leftward shifts in voltage-dependence of activation, and are inhibited by linopirdine (IC50 7.7 µM) and barium, at concentrations similar to those required to inhibit native M-currents. Stable heterologous expression in CHO cells, whole-cell voltage clamp, pharmacological characterization British journal of pharmacology High 11159685
2003 KCNQ3 co-immunoprecipitates with both KCNQ2 and KCNQ5 subunits in human temporal neocortex and hippocampus, but no association was detected between KCNQ2 and KCNQ5 directly. KCNQ5 protein is present in pyramidal and non-pyramidal neurons and a population of glial cells. Co-immunoprecipitation with specific antisera from human brain tissue, immunohistochemistry Neuroscience Medium 12890507
2005 Mouse KCNQ5 channels are modulated by extracellular zinc (potentiation, pH-dependent, EC50 21.8 µM at pH 7.4), inhibited by acidification (pKa 6.1), and regulated by small changes in cell volume (tonicity). Heterologous expression in Xenopus oocytes, two-electrode voltage clamp, pharmacological and ionic manipulation Brain research. Molecular brain research High 15963599
2006 In A7r5 rat aortic smooth muscle cells, vasopressin (AVP) inhibits KCNQ5 currents via a PKC-dependent mechanism, leading to membrane depolarization and action potential/Ca2+ spike generation. RNA interference knockdown of KCNQ5 reduced Kv currents and induced spontaneous action potentials. Patch clamp electrophysiology, RT-PCR, RNA interference, PKC inhibitor calphostin C, PKC activator PMA American journal of physiology. Heart and circulatory physiology High 17071736
2007 KCNQ5 is localized predominantly in excitatory (glutamatergic) synaptic endings of auditory brainstem neurons (cochlear nucleus, superior olivary complex, inferior colliculus), as shown by colocalization with synaptophysin/syntaxin but not with GlyT2 or GAD65 markers; it also localizes to dendritic compartments. High-resolution immunocytochemistry with double labeling (synaptic markers, MAP2), cochlear ablation to abolish immunoreactivity The Journal of comparative neurology High 17912742
2009 KCNE1 and KCNE3 accessory subunits specifically interact with KCNQ5 (Kv7.5): KCNE1 slows activation and suppresses inward rectification while increasing current amplitude; KCNE3 drastically inhibits KCNQ5 currents. No other KCNE subunits (KCNE2, 4, 5) significantly affect KCNQ5. Heterologous co-expression in Xenopus oocytes and HEK-293 cells, whole-cell voltage clamp, electrophysiological characterization Cellular physiology and biochemistry High 19910673
2009 Knockdown of KCNQ5 in A7r5 cells results in more positive resting membrane potentials and induces spontaneous action potential firing and Ca2+ spiking, demonstrating that KCNQ5 suppression alone is sufficient to excite vascular smooth muscle cells. AVP-induced activation of TRPC6 contributes additively to Ca2+ spiking. shRNA knockdown, patch clamp electrophysiology, fura-2 fluorescence Ca2+ imaging Cell calcium High 19246091
2010 KCNQ5 channels contribute to medium and slow afterhyperpolarization (mAHP and sAHP) currents in CA3 hippocampal neurons in a cell-type-specific manner. A dominant-negative KCNQ5 pore mutation renders homomeric and heteromeric KCNQ5-containing channels nonfunctional and significantly reduces mAHP and sAHP in CA3 but not CA1, correlating with higher KCNQ5 expression in CA3. Dominant-negative knock-in mouse model (KCNQ5dn/dn), whole-cell patch clamp in hippocampal slices, immunohistochemistry for subunit localization Proceedings of the National Academy of Sciences of the United States of America High 20534576
2010 KCNQ5 synaptic targeting in auditory brainstem neurons occurs at hearing onset (around P12-13), with a developmental shift from somatic to synaptic localization. Long-term synaptic maintenance after hearing onset depends on peripheral auditory nerve activity, as cochlear ablation caused redistribution from synaptic endings back to cell bodies. Immunocytochemistry during postnatal development, quantitative RT-PCR, cochlear ablation experiments The Journal of comparative neurology High 20151361
2010 Diclofenac differentially modulates KCNQ4 and KCNQ5: it inhibits KCNQ5 (reducing maximum conductance by 53%) but activates KCNQ4 (increasing conductance by 38%). Mutation of a basic lysine residue in the KCNQ5 voltage-sensing domain to the glycine present in KCNQ4 resulted in more effective block rather than conversion to activation. Heterologous expression in A7r5 cells, whole-cell patch clamp, site-directed mutagenesis Molecular pharmacology High 20876743
2011 KCNQ5 protein is expressed in the basal membrane of primate retinal pigment epithelium (RPE) where it contributes to the M-type K+ current. Application of XE991 eliminated the M-type current in freshly isolated RPE cells. KCNQ5 is also found in inner and outer plexiform layers and photoreceptor inner segments of the neural retina. RT-PCR, immunohistochemistry, in situ hybridization, whole-cell patch clamp with XE991 pharmacology in freshly isolated cells American journal of physiology. Cell physiology High 21795522
2012 Kv7.5 (KCNQ5) is the primary Kv7 subunit expressed in C-fibers (nociceptive neurons) and small-diameter dorsal root ganglion neurons (both IB4+ and TrkA+), where it is proposed to provide the primary M-current in these nociceptive neurons. In contrast, Kv7.2 and Kv7.3 localize to nodes of Ranvier and large sensory neuron cell bodies. Immunohistochemistry with subunit-specific antibodies in dorsal root ganglia and peripheral nerve sections The Journal of comparative neurology Medium 22134895
2012 Kv7.5 forms oligomeric channels specifically with KCNE1 and KCNE3 (but not other KCNEs), and KCNQ5 expression in cholesterol-rich membrane microdomains is very low. Kv7.5/KCNE1 and Kv7.5/KCNE3 oligomers do not localize to lipid rafts; Kv7.5 association impairs KCNE3 targeting to lipid raft microdomains. Co-immunoprecipitation, confocal microscopy, lipid raft isolation, FRAP in HEK293 cells Muscle & nerve Medium 22190306
2013 Kv7.4 and Kv7.5 proteins exist predominantly as functional heterotetramers (not Kv7.5 homomers) in cerebral arteries, mediating myogenic constriction in response to intravascular pressure increases. KCNQ5 siRNA reduces myogenic constriction but not CGRP-induced vasodilation, while KCNQ4 siRNA affects both. Proximity ligation assay, siRNA knockdown, isobaric myography, isometric tension recordings in rat middle cerebral artery Arteriosclerosis, thrombosis, and vascular biology High 24558103
2013 PKCα activation is sufficient to suppress endogenous Kv7 currents in smooth muscle cells. PKC-dependent phosphorylation differentially regulates Kv7.4 and Kv7.5: arginine vasopressin and PMA inhibit hKv7.5 and hKv7.4/7.5 but not hKv7.4 channels, associated with increased PKC-dependent phosphorylation of Kv7.5 but not Kv7.4. Proximity ligation assays demonstrate endogenous Kv7.4/Kv7.5 heteromers in vascular smooth muscle cells. Proximity ligation assay, inducible PKCα translocation system, dominant-negative subunit expression, patch clamp, phosphorylation assay in A7r5 and mesenteric artery myocytes The Journal of biological chemistry High 24297175
2013 KCNQ5 channels are expressed in intramuscular interstitial cells of Cajal (ICC-IM) but not ICC-MP of mouse colon; cholinergic muscarinic receptor stimulation with carbachol inhibits these Kv7 channels, which have a single-channel conductance of ~3.4 pS (normal K+) or ~18 pS (high K+). Single-channel patch clamp, XE991 pharmacology, single-cell RT-PCR, double immunohistochemistry Pflugers Archiv : European journal of physiology Medium 24375291
2013 KCNQ4 and KCNQ5 expression localizes in the postsynaptic calyx-forming neurons of vestibular ganglia (not in the innervated hair cells themselves), as demonstrated in KCNQ4-/-, KCNQ5dn/dn, and double-mutant mice. Loss of both channels results in altered vestibulo-ocular reflexes, indicating a role in modulating vestibular synaptic transmission. Immunohistochemistry in Kcnq4-/- and Kcnq5dn/dn mouse models, whole-cell recordings of vestibular hair cells, vestibulo-ocular reflex measurements The Journal of biological chemistry High 23408425
2014 Kv7.1 and Kv7.5 form functional heterotetrameric complexes in vascular smooth muscle. Kv7.1/Kv7.5 heteromers display distinct pharmacological characteristics from homomers, are highly retained at the endoplasmic reticulum, and predominant Kv7.5 expression promotes their release from lipid raft microdomains. Co-immunoprecipitation, FRET, FRAP, patch clamp in oocytes and mammalian cells, arterial tension measurements Arteriosclerosis, thrombosis, and vascular biology High 24855057
2015 KCNQ5 localizes to the postsynaptic site of inhibitory synapses on pyramidal cells and in interneurons of the hippocampus. Loss of KCNQ5 function (Kcnq5dn/dn mice) increases excitability of interneurons, enhances phasic and tonic inhibition, decreases electrical shunting of inhibitory postsynaptic currents, and in vivo reduces gamma and ripple oscillations with impaired spatial representations. Immunoelectron microscopy, whole-cell patch clamp in hippocampal slices, in vivo electrophysiology, place cell recordings in Kcnq5dn/dn mice Nature communications High 25649132
2015 β-adrenergic receptor activation enhances KCNQ5 (Kv7.5) currents in vascular smooth muscle via a cAMP/PKA pathway. Kv7.5 is 2-4 fold enhanced by PKA, whereas Kv7.4 is insensitive and Kv7.4/7.5 heteromers are only modestly enhanced, establishing Kv7.5 as the primary target for PKA-dependent regulation. Patch clamp in A7r5 and mesenteric artery myocytes, cAMP-elevating agents (forskolin, rolipram, isoproterenol), proximity ligation assay for PKA-dependent phosphorylation Molecular pharmacology High 26700561
2017 De novo heterozygous missense mutations in KCNQ5 cause intellectual disability and epileptic encephalopathy through both loss-of-function (reduced current, hyperpolarizing shift) and gain-of-function (shifted voltage dependence, altered kinetics) mechanisms, both leading to pathological neuronal excitability. Exome sequencing, heterologous expression in Xenopus oocytes, whole-cell voltage clamp, biophysical characterization of four variants American journal of human genetics High 28669405
2017 Histamine inhibits Kv7.5 currents in human airway smooth muscle cells via PKCα-dependent phosphorylation of serine 441 on the KCNQ5 C-terminus. This inhibition causes membrane depolarization and Ca2+ influx via L-type voltage-sensitive Ca2+ channels, contributing to bronchoconstriction. Patch clamp in human trachealis smooth muscle cells, PKC inhibitor Ro-31-8220, site-directed mutagenesis (S441A), PKCα knockdown, phosphorylation assay 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 (S53) on the amino terminus of KCNQ5. S53A mutation abolishes β-adrenergic/cAMP-induced current enhancement; S53D phosphomimetic reproduces activated channel behavior. C-terminal PKA phosphorylation sites are dispensable. Site-directed mutagenesis of 8 PKA phosphorylation sites, patch clamp in human ASMCs, β-adrenergic stimulation, MIT Scansite analysis International journal of molecular sciences High 30061510
2019 PKA-dependent phosphorylation of S53 on the KCNQ5 amino terminus increases its affinity for PIP2, thereby enhancing channel activity; PKC-dependent phosphorylation of the Kv7.5 C-terminus reduces PIP2 affinity and suppresses channel activity. The amino terminus is the critical domain conferring PKA responsiveness, distinct from the C-terminal PIP2 binding domain. Chimeric channel expression (Kv7.4/Kv7.5 swaps), Ci-VSP-induced PIP2 depletion, patch clamp, PMA and forskolin treatment in smooth muscle cells Molecular pharmacology High 31871302
2020 Heteromeric Kv7.4/Kv7.5 channels constrained to a 2:2 stoichiometry with alternating α-subunits best reproduce biophysical and pharmacological characteristics of native smooth muscle M-currents in mesenteric artery myocytes. Concatenated dimer and tetramer constructs of Kv7.4 and Kv7.5, patch clamp in A7r5 smooth muscle cells Frontiers in physiology High 32903335
2022 KCNQ2 and KCNQ5 form functional heteromeric channels independent of KCNQ3. KCNQ2/5 tandems (via split-intein trans-splicing) form functional channels in heterologous cells, and mass spectrometry of native brain channels confirmed endogenous KCNQ2-KCNQ5 association even in the absence of KCNQ3. Data are also consistent with KCNQ2/3/5 trimeric heteromers. Split-intein protein trans-splicing to generate KCNQ2/5 tandems, heterologous expression, whole-cell patch clamp, mass spectrometry of native brain channel complexes Proceedings of the National Academy of Sciences of the United States of America High 35320039
2022 Two KCNQ5 pore variants (G347S and G347A) causing developmental and epileptic encephalopathy produce gain-of-function through a >10-fold increase in maximal current density, a voltage-independent current component, slower deactivation, and hyperpolarized activation. Nonstationary noise analysis showed the mechanism is an increase in single-channel open probability without changes in membrane abundance or single-channel conductance; this effect is insensitive to PIP2 manipulation. Heterologous expression in HEK cells, whole-cell and nonstationary noise analysis, Western blot for membrane abundance, PIP2 manipulation Proceedings of the National Academy of Sciences of the United States of America High 35377796
2022 All eight tested KCNQ5 missense variants from patients with neurodevelopmental disorders cause gain-of-function (hyperpolarized V50 or slowed deactivation), while two nonsense variants are loss-of-function. A severe GOF allele (P369T) extends dominant GOF to heteromeric KCNQ5/KCNQ3 channels. Kcnq5 loss-of-function CRISPR mice exhibit handling- and thermal-induced seizures and epileptiform EEGs. Whole exome sequencing, electrophysiology in HEK293/CHO cells, CRISPR/Cas9 mouse models, EEG recording Journal of neurophysiology High 35583973
2022 Three KCNQ5 missense variants identified in genetic generalized epilepsy families show strongly decreased current density (loss-of-function), with three variants displaying dominant-negative effects on co-expressed wild-type KCNQ5 or KCNQ5/KCNQ3. The R359C variant specifically alters PI(4,5)P2 interaction. Surface expression (by biotinylation assay) was normal for all variants. Patch clamp in mammalian cells, biotinylation surface expression assay, phospholipid overlay assay, homology modelling, next-generation sequencing in 1292 GGE families EBioMedicine High 36088682
2023 Perivascular adipose tissue (PVAT) releases oxylipins that activate smooth muscle KCNQ5 (KV7.5) channels, causing membrane hyperpolarization and vasorelaxation of small arteries, thereby regulating blood pressure. This was demonstrated using multiple Kcnq5 genetic mouse models (Kcnq5-/-, Kcnq5dn/dn, and double knockouts). Wire-myography, patch clamp, sharp-electrode membrane potential recordings, targeted lipidomics, RNA-Seq, multiple Kcnq5 genetic mouse models, telemetry blood pressure Hypertension (Dallas, Tex. : 1979) High 38354270
2024 Retigabine and gabapentin restore M-current amplitude in HEK cells expressing dominant-negative KCNQ5 R359C (homomeric or heteromeric), and reduce neuronal firing elevated by R359C overexpression, establishing KV7 channel openers as pharmacological tools to rescue KCNQ5 loss-of-function pathology. Whole-cell patch clamp in HEK cells and neurons, KV7 channel openers (retigabine, gabapentin, ZnCl2), dominant-negative R359C overexpression model Neuropharmacology Medium 38428481
2026 GADD45A recruits TET1 to the CpG islands of the KCNQ5 promoter via recognition of R-loop structures formed by a nearby antisense lncRNA, enabling DNA demethylation and transcriptional activation of KCNQ5 in cortical excitatory neurons. Absence of GADD45A reduces KCNQ5 expression, impairs M-current, and increases neuronal firing frequency. Gadd45a knockout mice, in vivo electrophysiology, ChIP/TET1 recruitment assays, R-loop structure analysis, promoter methylation analysis in cortical neurons 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 325 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
2001 Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. British journal of pharmacology 81 11159685
2014 Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity. Arteriosclerosis, thrombosis, and vascular biology 78 24558103
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 61 17071736
2013 Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. The Journal of biological chemistry 60 24297175
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 53 26700561
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
2015 KCNQ5 K(+) channels control hippocampal synaptic inhibition and fast network oscillations. Nature communications 52 25649132
2010 Diclofenac distinguishes among homomeric and heteromeric potassium channels composed of KCNQ4 and KCNQ5 subunits. Molecular pharmacology 50 20876743
2013 Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders. Frontiers in genetics 42 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 37 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 33 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 30 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 21 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 18 28884119
2018 Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells. International journal of molecular sciences 17 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
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
2023 KCNQ5 Controls Perivascular Adipose Tissue-Mediated Vasodilation. Hypertension (Dallas, Tex. : 1979) 6 38354270
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 4 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