Affinage

KCNQ3

Potassium voltage-gated channel subfamily KQT member 3 · UniProt O43525

Length
872 aa
Mass
96.7 kDa
Annotated
2026-06-10
93 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNQ3 (Kv7.3) is a voltage-gated K+ channel subunit that preferentially co-assembles with KCNQ2 into heterotetrameric channels generating the slowly-activating, non-inactivating neuronal M-current that governs subthreshold excitability (PMID:9836639, PMID:9872318). Atomic force microscopy establishes a predominantly 2:2 KCNQ2/KCNQ3 stoichiometry with non-fixed subunit arrangement, and KCNQ3 also partners with KCNQ5 (PMID:22334706, PMID:17322297), while KCNQ2 can independently associate with KCNQ5, indicating channel composition is more diverse than a single canonical heteromer (PMID:35320039). Within the heteromer KCNQ3 contributes high open probability and shapes gating, whereas KCNQ2 is the obligatory subunit driving surface expression and excitability control (PMID:11432988, PMID:24719109). KCNQ3 surface delivery is gated by the pore-vestibule residue A315, which enforces ER retention of homomers until KCNQ2 co-assembly permits trafficking; the A315T substitution unlocks both a conductive pore state and KCNQ2-independent membrane export, and pore helix-S6 contacts (A315-F344, I312) control conductance (PMID:18790849, PMID:20610766, PMID:22713565, PMID:22713564). Assembled channels are concentrated at axon initial segments via AnkyrinG-dependent immobilization following bidirectional axonal membrane diffusion, with C-terminal domains tuning targeting efficiency (PMID:16735477, PMID:32903174, PMID:32116557). The M-current is suppressed through a Gq/11-PLC-PIP2 hydrolysis cascade downstream of M1 muscarinic receptors (PMID:15173220, PMID:10684873), and is further tuned post-translationally by Nedd4-2-mediated ubiquitination (opposed by SGK-1), SUMOylation reversed by SENP2, phosphorylation of an S4-S5 loop site shared across KCNQs, and subunit-specific apo-calmodulin modulation of PIP2 sensitivity (PMID:17322297, PMID:18463232, PMID:34509475, PMID:16319223, PMID:28507506). GABA directly binds and activates KCNQ3-containing channels through a W266 site, a non-canonical neurotransmitter-channel interaction with behavioral consequences (PMID:37305551). Loss-of-function and dominant-negative pore mutations (W309R) and a homozygous frameshift abolishing channel function cause benign neonatal epilepsy and severe neonatal-onset epileptic encephalopathy, whereas gain-of-function voltage-sensor mutations (R230C) stabilize the activated state to produce constitutive opening and epileptic encephalopathy (PMID:18425618, PMID:31440727, PMID:25740509, PMID:29383681, PMID:30578330). Beyond neuronal excitability, KCNQ3 controls intrinsic excitability of hypothalamic AgRP neurons and hippocampal theta-coordinated bursting, and is transcriptionally repressed in DRG neurons during cancer pain (PMID:33766732, PMID:34376649, PMID:39192337, PMID:40730259).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1998 High

    Established the molecular identity of the long-sought neuronal M-current by showing KCNQ2 and KCNQ3 co-assemble into heteromers reproducing its biophysics and pharmacology.

    Evidence Xenopus oocyte expression, electrophysiology, pharmacology and in situ hybridization; whole-cell patch clamp with mutagenesis

    PMID:9836639 PMID:9872318

    Open questions at the time
    • Stoichiometry of the heteromer not yet defined
    • Surface trafficking mechanism unresolved
    • In vivo native channel composition not addressed
  2. 2000 High

    Showed that the dramatic current increase on co-assembly is driven by enhanced surface expression and that muscarinic suppression is independent of Ca2+ and PKC, narrowing the search for the diffusible messenger.

    Evidence Oocyte noise analysis, single-channel recording and surface assays; tsA-201 patch clamp with Ca2+ imaging and pharmacological dissection

    PMID:10684873 PMID:10788442

    Open questions at the time
    • Identity of the messenger linking Gq to channels not yet established
    • Molecular determinants of co-assembly-dependent trafficking unknown
  3. 2001 High

    Defined the functional division of labor: KCNQ3 sets open probability and conductance while KCNQ2 primarily controls surface expression.

    Evidence Cell-attached and perforated-patch single-channel recordings in CHO cells

    PMID:11432988

    Open questions at the time
    • Structural basis of subunit-specific conductance differences not resolved
    • Does not address native stoichiometry in neurons
  4. 2003 High

    Quantified heteromer composition and mapped the C-terminal domains required for KCNQ2/KCNQ3 functional interaction.

    Evidence TEA inhibition with tandem constructs, qPCR, ICC; chimeric channel analysis in oocytes

    PMID:12640002 PMID:12832524

    Open questions at the time
    • 1:1 stoichiometry estimate later refined by direct imaging
    • Atomic interface between subunits not defined
  5. 2004 High

    Resolved the muscarinic suppression mechanism as a Gq/11-PLC-PIP2 hydrolysis cascade that depletes PIP2 from the channel.

    Evidence Patch clamp with PIP2 optical probe, constitutively active Galpha mutants, RGS2 and GDPbetaS in tsA-201 cells

    PMID:15173220

    Open questions at the time
    • Channel PIP2 binding site not mapped here
    • Quantitative coupling between receptor occupancy and current not fully defined
  6. 2005 High

    Identified in vivo phosphorylation sites on the assembled channel, including a shared S4-S5 loop site mediating inhibition and a silent KCNQ3 tetramerization-domain site.

    Evidence Mass spectrometry of native channels with mutagenesis and electrophysiology

    PMID:16319223

    Open questions at the time
    • Responsible kinases not identified
    • Physiological stimulus driving phosphorylation unknown
  7. 2006 High

    Demonstrated polarized axonal/AIS targeting of M-channels and that AnkyrinG-binding motifs on both subunits are required, linking trafficking defects to BFNC mutations.

    Evidence Live surface imaging, truncation/chimera domain mapping and AnkyrinG-motif mutagenesis in neurons

    PMID:16735477

    Open questions at the time
    • Dynamic trafficking route to the AIS not yet observed
    • Distal axonal targeting determinants partially defined
  8. 2008 High

    Defined the A315 pore-vestibule residue as the molecular switch that keeps KCNQ3 homomers electrically silent, with A315T unlocking conduction.

    Evidence Biotinylation, TIRF imaging, mutagenesis, homology modeling and electrophysiology

    PMID:18790849

    Open questions at the time
    • Whether A315 also controls trafficking not yet tested here
    • Structural model based on homology, not experimental structure
  9. 2007 High

    Established Nedd4-2 as a direct E3 ligase that ubiquitinates and downregulates KCNQ3-containing channels via its C-terminus, and SGK-1 as a counter-regulator.

    Evidence GST pulldown, Co-IP, ubiquitination assays, oocyte electrophysiology; surface biotinylation with kinase-dead mutants

    PMID:17322297 PMID:18463232

    Open questions at the time
    • Endogenous signals controlling Nedd4-2/SGK-1 balance unclear
    • SGK-1 evidence from single lab
  10. 2008 High

    Showed in native neurons that KCNQ2 and KCNQ3 contribute to medium afterhyperpolarization in a region-specific manner.

    Evidence Whole-cell patch clamp in Kcnq2- and Kcnq3-knockout mouse hippocampal neurons with pharmacology

    PMID:19060215

    Open questions at the time
    • Mechanism of hippocalcin coupling not resolved
    • CA1 redundancy not explained
  11. 2010 High

    Established A315 as an ER-retention checkpoint that enforces KCNQ2-dependent surface delivery of KCNQ3, governing subunit composition of surface M-channels.

    Evidence Subcellular fractionation, confocal imaging, mutagenesis and electrophysiology

    PMID:20610766

    Open questions at the time
    • ER quality-control machinery recognizing A315 not identified
    • Link to conductance gating function of A315 not fully integrated
  12. 2012 High

    Directly visualized heteromer architecture as predominantly 2:2 with random subunit arrangement and variable stoichiometry, and refined pore-helix/S6 determinants of current amplitude.

    Evidence Atomic force microscopy with antibody decoration; mutagenesis, TIRF and homology modeling

    PMID:22334706 PMID:22713564 PMID:22713565

    Open questions at the time
    • Functional consequence of variable stoichiometry in neurons unknown
    • Pore mechanism inferred from homology models
  13. 2014 High

    Defined KCNQ2 as the obligatory M-channel subunit in vivo, with KCNQ3 loss producing only modest secondary effects.

    Evidence Conditional knockout mice with EEG, patch clamp, Western blot and KCNQ-activator pharmacology

    PMID:24719109

    Open questions at the time
    • Distinct contribution of KCNQ3 vs KCNQ5 to residual current not fully separated
  14. 2015 High

    Defined the gain-of-function disease mechanism: voltage-sensor mutation R230C stabilizes the activated state and causes constitutive opening leading to epileptic encephalopathy.

    Evidence Patch clamp, multistate structural modeling and disulfide trapping; helix C-D linker deletion with TIRF

    PMID:25740509 PMID:26692086

    Open questions at the time
    • In vivo seizure phenotype of R230C not modeled here
    • Endogenous regulation of voltage-sensor stability unaddressed
  15. 2018 High

    Mechanistically separated loss- and gain-of-function disease variants, showing additive PIP2-coupling defects (V359L, D542N) versus constitutive opening from charge/size at R230.

    Evidence Patch clamp, voltage-clamp fluorometry and unnatural-amino-acid mutagenesis

    PMID:29383681 PMID:30578330

    Open questions at the time
    • Compound-heterozygous phenotype-genotype mapping limited
    • Tissue-level consequences not assayed
  16. 2019 High

    Provided definitive human genetic proof that complete KCNQ3 loss causes severe neonatal-onset pharmacodependent epilepsy with intellectual disability.

    Evidence Exome sequencing, qRT-PCR, Western blot, immunofluorescence and patch clamp from patient material

    PMID:31440727

    Open questions at the time
    • Single family; phenotypic spectrum of biallelic loss not broadly defined
  17. 2020 High

    Resolved the trafficking route to the AIS, showing Kv7.3 reaches somatic/terminal membrane then diffuses bidirectionally until AnkyrinG immobilizes it, with C-terminal domains tuning efficiency.

    Evidence Live imaging, FRAP and single-molecule tracking in neurons; chimeric domain mapping

    PMID:32116557 PMID:32903174

    Open questions at the time
    • Regulation of diffusion-to-trapping transition unclear
    • C-terminal AIS domain hierarchy from single lab
  18. 2021 High

    Expanded KCNQ3 physiological roles beyond cortex to hypothalamic energy homeostasis, hippocampal theta-coordinated bursting, and peripheral pain resilience, and defined SUMOylation as a regulator of assembly and PIP2 binding.

    Evidence AAV-CRISPR knockdown with patch clamp and behavior; Kcnq3-KO in vivo recording with optogenetics; iPSC sensory neurons with dynamic clamp; SENP2-deficient mice with biochemistry

    PMID:33766732 PMID:34376649 PMID:34509475 PMID:34557669

    Open questions at the time
    • SUMOylation regulation studied in single lab
    • D755N pain-resilience variant from single cohort
    • Circuit basis of theta entrainment incompletely mapped
  19. 2022 High

    Revealed greater channel compositional diversity (KCNQ2/KCNQ5 without KCNQ3) and identified subunit-selective pharmacology (triclosan activates KCNQ3 via the voltage sensor).

    Evidence Split-intein tandems with native mass spectrometry; patch clamp with mutagenesis and docking

    PMID:35320039 PMID:35459955

    Open questions at the time
    • Functional weight of KCNQ2/5 channels in vivo unclear
    • Triclosan binding site inferred from docking
  20. 2023 Medium

    Demonstrated a non-canonical mechanism in which GABA directly binds and activates KCNQ3-containing channels through a W266 site with sex-specific behavioral consequences.

    Evidence W266L knock-in mouse with behavioral testing and neuronal activity measurement

    PMID:37305551

    Open questions at the time
    • Direct binding affinity and structural basis not resolved
    • Single lab
  21. 2024 Medium

    Linked KCNQ3 to disease beyond excitability through transcriptional repression in pain (HDAC2/MeCP2/Sin3A) and a proliferative RAS/MAPK signaling role in thyroid cancer.

    Evidence ChIP and Co-IP with DRG electrophysiology and in vivo pain model; Co-IP/MS, ChIP-qPCR and xenograft assays

    PMID:39192337 PMID:41250218

    Open questions at the time
    • Channel-independent vs channel-dependent contributions to cancer signaling unclear
    • Single-lab findings
  22. 2025 Medium

    Defined DNMT3a-mediated DNA methylation as an additional epigenetic route repressing kcnq2/kcnq3 in cancer pain, downstream of VEGFA-PI3K-Akt-C/EBPbeta signaling.

    Evidence In vivo bone cancer pain model, DNMT3a knockdown, ChIP, luciferase reporters and DRG electrophysiology

    PMID:40730259

    Open questions at the time
    • Convergence with HDAC2 repression pathway not integrated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How channel functionality, AIS trafficking dynamics, and the regulatory PTM network (SUMOylation, ubiquitination, phosphorylation, calmodulin) are coordinated at single-molecule resolution in living neurons remains unresolved.
  • No experimental atomic structure of KCNQ3-containing channels in the timeline
  • Integration of PTM regulation with native trafficking not established
  • Coupling of low-activity mutations to AIS diffusion based on preprint only

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2
Partners
ANKYRINGCALMODULINGRB2KCNE2KCNQ2KCNQ5NEDD4LSGK1
Complex memberships
KCNQ2/KCNQ3 heterotetramer (M-channel)KCNQ3/KCNQ5 heteromer

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 KCNQ2 and KCNQ3 subunits co-express in brain with overlapping patterns and form heteromeric channels whose biophysical properties, pharmacological sensitivity, and expression pattern correspond to the native neuronal M-current. Xenopus oocyte expression, electrophysiology, pharmacology, in situ hybridization Science High 9836639
1998 KCNQ2/KCNQ3 heteromeric channels produce currents at least 10-fold larger than respective homomeric channels; KCNQ2/KCNQ3 currents are increased by intracellular cyclic AMP via a phosphorylation site on KCNQ2's amino terminus; BFNC mutations cause loss of function without dominant-negative effect on heteromers. Xenopus oocyte expression, whole-cell patch clamp, site-directed mutagenesis Nature High 9872318
2000 Muscarinic modulation of KCNQ2/KCNQ3 heteromeric channels reconstituted with M1 receptors mirrors native M-current modulation; modulation is not blocked by Ca2+ chelation or broad-spectrum PKC inhibition (staurosporine), ruling out Ca2+ and protein kinases as diffusible messengers; both homomeric KCNQ2 and KCNQ3 subunits are individually susceptible to oxo-M modulation. Whole-cell patch clamp, indo-1 Ca2+ imaging, pharmacological dissection in tsA-201 cells The Journal of Neuroscience High 10684873
2000 Co-expression of KCNQ2 and KCNQ3 increases surface expression of both subunits (KCNQ2 ~5-fold, KCNQ3 >10-fold), and the current increase upon co-expression is predominantly due to increased surface expression; a truncated KCNQ2 BFNC mutant fails to reach the surface and fails to stimulate KCNQ3 surface expression. Xenopus oocyte expression, noise analysis, single-channel recordings, surface expression assays The Journal of Biological Chemistry High 10788442
2000 A novel KCNQ3 pore-loop mutation (W309R) causes BFNC2 by disrupting the conserved tryptophan in the P-loop that holds the channel pore open. Sequencing, co-segregation analysis, functional inference from conserved pore residue Annals of Neurology Medium 10852552
2000 KCNE2 (MinK-related peptide 1) associates with KCNQ2 and/or KCNQ3 subunits in brain and, when co-expressed in COS cells, accelerates deactivation kinetics of KCNQ2 and the KCNQ2/KCNQ3 complex. Co-immunoprecipitation, transient transfection, electrophysiology FEBS Letters Medium 11034315
2001 Single-channel recordings show that homomeric KCNQ3 channels have the same slope conductance (~9 pS) as KCNQ2/KCNQ3 heteromers but higher open probability, while KCNQ2 homomers have lower conductance and open probability; KCNQ2 is thus primarily responsible for surface expression and KCNQ3 for modifying channel function. Cell-attached patch clamp, perforated-patch whole-cell recordings in CHO cells The Journal of Physiology High 11432988
2002 KCNQ3 antibodies confirm KCNQ2 and KCNQ3 subunits are present at SCG and hippocampal neurons; N-ethylmaleimide augments KCNQ2 but not KCNQ3 currents through a cysteine at position C242 of KCNQ2, localizing a pharmacological action to KCNQ2. Specific antibody labeling, site-directed mutagenesis, patch clamp in tsA-201 cells and SCG neurons British Journal of Pharmacology Medium 12466226
2002 A BFNC KCNQ2 mutation (R214W) in the S4 voltage-sensing domain causes slower channel opening, faster closing, and decreased voltage sensitivity without reducing maximal current or surface expression, demonstrating that gating alterations (not just reduced current) can cause neonatal epilepsy. Patch-clamp electrophysiology of heteromeric KCNQ2/KCNQ3 channels in mammalian cells The Journal of Neuroscience Medium 11784811
2003 KCNQ2 and KCNQ3 co-express with 1:1 stoichiometry in CHO cells and in native SCG neurons, as determined by TEA block curves compared against a KCNQ3/2 tandem construct. TEA concentration-inhibition analysis, tandem-construct pharmacology, quantitative PCR, immunocytochemistry The Journal of Neuroscience High 12832524
2003 The C-terminal A-domain (~80 amino acids) plus either the B-domain or proximal C-terminus between S6 and the A-domain is required for functional interaction between KCNQ2 and KCNQ3; the proximal part of the KCNQ3 C-terminus controls current amplitude and depolarizing shift of activation in chimeric channels. Chimeric channel construction, Xenopus oocyte expression, electrophysiology The Journal of Physiology Medium 12640002
2004 M1 muscarinic receptor-mediated suppression of KCNQ2/KCNQ3 current proceeds through a classical Gq G-protein cycle: Gq/11 (not G13) activation → PLC stimulation → PIP2 hydrolysis → PIP2 dissociation from KCNQ channels, as shown by constitutively active Galpha mutants, RGS2 overexpression, GDPbetaS dialysis, and a PIP2 optical probe. Whole-cell patch clamp, confocal microscopy with PIP2 optical probe, mutagenesis of G-protein subunits, RGS2 co-expression in tsA-201 cells The Journal of General Physiology High 15173220
2005 Mass spectrometry of in vivo KCNQ2/KCNQ3 channels identifies two phosphorylation sites: one KCNQ3-specific site in the C-terminal tetramerization domain (functionally silent) and one in the S4-S5 intracellular loop shared by all KCNQs that acts as a mechanism of channel inhibition. Mass spectrometry, site-directed mutagenesis, electrophysiology PNAS High 16319223
2006 KCNQ2/KCNQ3 channels are preferentially expressed on axonal surfaces including axon initial segments and more distal axon; AIS targeting requires ankyrin-G binding motifs on both KCNQ2 and KCNQ3, while distal axonal targeting requires membrane-proximal and A-domain sequences in KCNQ2 C-terminal tail; several BFNC mutations disrupt surface expression or polarized distribution. Live imaging of surface-expressed channels in neurons, domain mapping with truncation/chimeras, ankyrin-G binding motif mutagenesis PNAS High 16735477
2007 Nedd4-2 ubiquitin ligase (but not Nedd4) directly interacts with KCNQ3 C-terminal region, ubiquitinates KCNQ2/KCNQ3, and reduces K+ current amplitudes of KCNQ2/3 and KCNQ3/5 heteromeric channels; the KCNQ3 C-terminus is required for this regulation. GST pulldown, co-immunoprecipitation, ubiquitination assay in transfected cells, Xenopus oocyte electrophysiology The Journal of Biological Chemistry High 17322297
2008 SGK-1 kinase upregulates KCNQ2/3 and KCNQ3/5 K+ current amplitudes and increases cell surface levels of KCNQ2/3 channels; this effect is kinase-activity dependent and is abrogated by co-expression of Nedd4-2 S448A mutant, suggesting SGK-1 acts via phosphorylation of Nedd4-2 to reduce ubiquitination-mediated channel downregulation. Xenopus oocyte electrophysiology, surface biotinylation in transfected cells, kinase-dead mutant American Journal of Physiology. Cell Physiology Medium 18463232
2008 KCNQ3 homomers are well-expressed at the plasma membrane but most wild-type channels are functionally silent; the A315 residue in the pore vestibule (alanine in KCNQ3 vs. threonine in other KCNQs) governs this silencing. The A315T mutation unlocks channels into a conductive state by stabilizing a critical pore helix-selectivity filter interaction, increasing current density ~10-fold. Biotinylation, TIRF imaging, site-directed mutagenesis, homology modeling, electrophysiology Biophysical Journal High 18790849
2008 KCNQ3 homomeric channels carrying the BFNC W309R pore-helix mutation lose K+ current; heteromeric KCNQ2/KCNQ3-W309R channels show dominant-negative suppression and altered gating; homology modeling shows the R side chain cannot form hydrogen bonds with the selectivity filter tyrosine. Patch clamp in HEK293 cells, homology modeling The Journal of Membrane Biology Medium 18425618
2008 KCNQ3 and KCNQ2 both contribute to the apamin-insensitive medium afterhyperpolarization (ImAHP) in dentate granule cells (~50% reduction in knockouts), but CA1 pyramidal neurons show no impairment in either single knockout; KCNQ channels also contribute to the slow afterhyperpolarization (IsAHP), with hippocalcin as a potential calcium sensor linking the two processes. Whole-cell patch clamp in KCNQ3- and KCNQ2-knockout mouse hippocampal neurons, pharmacological manipulation PNAS High 19060215
2010 Wild-type KCNQ3 expressed alone is retained in the endoplasmic reticulum and requires assembly with KCNQ2 to exit; the A315 pore residue controls ER retention such that the A315T substitution enables efficient plasma membrane trafficking of KCNQ3 independent of KCNQ2, revealing A315 as a molecular checkpoint governing subunit composition of surface M-channels. Subcellular fractionation, immunofluorescence/confocal microscopy, site-directed mutagenesis, electrophysiology The Journal of Neuroscience High 20610766
2012 Atomic force microscopy with subunit-specific antibodies demonstrates that Kv7.2/Kv7.3 heteromers assemble as tetramers with predominantly 2:2 stoichiometry and random (non-fixed) subunit arrangement; when DNA ratios are varied, stoichiometry is variable and not fixed. Atomic force microscopy, immunoaffinity isolation, antibody decoration The Journal of Biological Chemistry High 22334706
2012 Pore helix-S6 interactions govern KCNQ3 current amplitudes: mutations at F344 in S6 dramatically decrease currents by disrupting interaction with A315 in the pore helix; this mechanism is more important than C-terminal effects on current amplitude. Site-directed mutagenesis, TIRF imaging, homology modeling, patch clamp Biophysical Journal Medium 22713565
2012 Mutations at position I312 in the pore helix of KCNQ3 (I312E, I312K, I312R) dramatically decrease homomeric and heteromeric KCNQ2/3 currents by locking the selectivity filter in a nonconductive conformation, as supported by homology modeling. Site-directed mutagenesis, TIRF imaging, patch clamp, homology modeling Biophysical Journal Medium 22713564
2014 Conditional deletion of Kcnq2 from cortical pyramidal neurons causes abnormal EEG and early death; loss of KCNQ2 secondarily reduces KCNQ3 and KCNQ5 protein levels, whereas loss of Kcnq3 causes only modest reduction of other KCNQ channels; KCNQ allosteric activators dampen excitability in Kcnq3-null but not Kcnq2-null neurons, demonstrating that KCNQ2 is the obligatory subunit. Conditional knockout mice, EEG, whole-cell patch clamp, biochemistry (Western blot), pharmacology The Journal of Neuroscience High 24719109
2015 Gain-of-function mutations in the voltage-sensing domain of Kv7.3 (R230C) stabilize the activated state by disrupting a network of electrostatic interactions with neighboring negatively charged residues in the resting state, confirmed by disulfide trapping; this causes channels to remain open throughout the physiological voltage range and leads to epileptic encephalopathy. Patch clamp in mammalian cells, multistate structural modeling, disulfide trapping experiments The Journal of Neuroscience High 25740509
2015 The extra residues in the helix C-D linker of KCNQ3 C-terminus reduce channel surface expression by causing ER retention; deletion of these residues increases KCNQ3 current by increasing plasma membrane expression, as confirmed by TIRF and plasma membrane protein assays. Site-directed deletion mutagenesis, TIRF imaging, plasma membrane protein assay, confocal microscopy PLoS One Medium 26692086
2017 Apo-calmodulin (calcium-independent) differentially regulates PI(4,5)P2 sensitivity of Kv7.2 and Kv7.3: it increases Kv7.2 current density and reduces its PIP2 depletion sensitivity, but has no potentiating effect on Kv7.3 homomers; for Kv7.2/3 heteromers, CaM reduces PI(4,5)P2 sensitivity; this regulation is subunit-specific. Whole-cell patch clamp, DrVSP-mediated PIP2 depletion, CaM sponge, PI(4)P5-kinase overexpression, CaM1234 mutant Frontiers in Molecular Neuroscience Medium 28507506
2018 Two KCNQ3 missense mutations (V359L and D542N) found in compound heterozygosis each decrease PIP2-dependent current regulation with additive effects; the R230C voltage-sensor mutation in KCNQ3 shifts the open/closed gate to very negative potentials, allowing S4 movement while causing constitutive opening; arginine at position 230 governs this through both charge and side chain size. Patch-clamp recordings, voltage clamp fluorometry, site-directed mutagenesis with natural and unnatural amino acids Molecular Neurobiology / The Journal of General Physiology High 29383681 30578330
2019 A homozygous frameshift KCNQ3 variant (c.1599dup) causes nonsense-mediated mRNA decay, dramatically reduces KCNQ3 protein in patient fibroblasts, and fully abolishes homomeric and KCNQ2/KCNQ3 heteromeric channel function, resulting in severe neonatal-onset pharmacodependent epilepsy and intellectual disability. Exome sequencing, qRT-PCR, Western blot, immunofluorescence, whole-cell patch clamp electrophysiology Epilepsia Open High 31440727
2020 Kv7.3 is delivered to somatic and axon terminal plasma membranes before diffusing bidirectionally along the axonal membrane until immobilized at the AIS through interaction with AnkyrinG, revealing the trafficking pathway for AIS localization. Live imaging of fluorescent-tagged Kv7.3 in neurons, FRAP, single-molecule tracking eLife High 32903174
2020 Multiple C-terminal domains of Kv7.3 modulate AIS localization: a membrane proximal domain reduces AIS localization efficiency while helix D increases and stabilizes it; neither domain is absolutely required but both regulate the relative efficiency of AIS targeting. Chimeric channel expression in cultured hippocampal neurons, confocal microscopy Frontiers in Cellular Neuroscience Medium 32116557
2021 CRISPR knockdown of Kcnq3 in NPY/AgRP neurons attenuates M-current, increases neuronal depolarization, raises input resistance, and reduces current threshold for action potentials, demonstrating KCNQ3's role in controlling intrinsic excitability of hypothalamic neurons and energy homeostasis (reduced locomotor activity). AAV-CRISPR in vivo knockdown, single-cell qPCR, whole-cell patch clamp, open-field testing Molecular Metabolism Medium 33766732
2021 Hyper-SUMOylation of Kv7.3 (and Kv7.2) reduces PIP2 binding and inhibits CaM1-mediated assembly; SENP2 deSUMOylase removes SUMO modifications to restore channel assembly and M-current; retigabine reduces SAE1 transcription and inhibits KCNQ3 SUMOylation. SENP2-deficient mice, co-immunoprecipitation, mutagenesis of SUMOylation sites, patch clamp, Western blot The Journal of Biological Chemistry Medium 34509475
2021 A gain-of-function missense variant (D755N) in KCNQ3 (Kv7.3) co-expressed with Kv7.2 produces larger M-currents than wild-type Kv7.2/Kv7.3, and dynamic clamp modeling confirmed this reduces DRG neuron excitability, identifying KCNQ3 as a pain resilience factor in peripheral sensory neurons. Voltage-clamp recordings in heterologous cells, iPSC-derived sensory neurons, dynamic clamp Brain Communications Medium 34557669
2021 In mice lacking Kcnq3, hippocampal pyramidal cell complex spike bursts are less coordinated by the theta rhythm during spatial navigation; place fields of single spikes are smaller; joint activity of medial septal GABAergic and cholinergic inputs (not either alone) is required for burst entrainment. Kcnq3 knockout mice, in vivo electrophysiology during spatial navigation, optogenetic manipulation of septal inputs Nature Communications High 34376649
2022 KCNQ2 associates with KCNQ5 in native brain channels even in the absence of KCNQ3, as shown by split-intein KCNQ2/5 tandems forming functional channels and mass spectrometry of native complexes, demonstrating that KCNQ channel composition is more diverse than the canonical KCNQ2/3 or KCNQ3/5 model. Split-intein protein trans-splicing (tandem constructs), heterologous expression electrophysiology, native brain mass spectrometry PNAS High 35320039
2022 Triclosan activates KCNQ3 but not KCNQ2 channels by inducing a voltage shift in activation, increasing conductance, and slowing channel closing; site-directed mutagenesis and molecular docking suggest the binding site is in the voltage sensor domain; the response is PIP2-independent. Patch clamp, site-directed mutagenesis, molecular docking Pflügers Archiv Medium 35459955
2024 HDAC2 forms a corepressor complex with MeCP2 and Sin3A to transcriptionally repress kcnq2/kcnq3 genes in DRG neurons; upstream, EREG/EGFR-ERK-Runx1 signaling activates HDAC2-mediated transcriptional repression, leading to neuronal hyperexcitability and bone cancer pain. ChIP, co-IP, qPCR, DRG neuron electrophysiology, in vivo bone cancer pain model Cell Communication and Signaling Medium 39192337
2024 KCNQ3 interacts with GAREM1, GRB2, and SOS1 and activates RAS/RAF/MAPK signaling to promote papillary thyroid cancer cell proliferation and migration; E2 enhances KCNQ3 transcription by ESR1 binding to the KCNQ3 promoter. Co-immunoprecipitation, mass spectrometry, ChIP-qPCR, wound-healing/transwell assays, xenograft in vivo Cancer Cell International Medium 41250218
2025 DNMT3a-mediated DNA methylation transcriptionally represses kcnq2/kcnq3 in DRG neurons in bone cancer pain; C/EBPβ activates Dnmt3a transcription; VEGFA/VEGFR2-PI3K-Akt-C/EBPβ signaling is the upstream pathway driving this epigenetic suppression. In vivo bone cancer pain model, DNMT3a inhibition/knockdown, ChIP, luciferase reporter assays, DRG neuron electrophysiology The Journal of Pain Medium 40730259
2023 GABA directly binds to and activates channels containing KCNQ3 through a specific binding site (W266); mice with mutated KCNQ3 GABA binding site (W266L) show sex-specific behavioral phenotypes including reduced nociception and stress responses, altered lateral habenula and visual cortex activity, demonstrating a non-canonical direct neurotransmitter-channel interaction. Knock-in mouse model, behavioral testing, neuronal activity measurement Frontiers in Molecular Neuroscience Medium 37305551
2024 Low-activity mutations in the KCNQ3 subunit affect all 3D dynamics (lateral diffusion and exo/endocytosis) of KCNQ2/3 at the AIS by disrupting interaction with ankyrin-G, coupling channel functionality to AIS trafficking regulation. Single-molecule and multi-molecule live imaging, endocytosis/exocytosis assays in neurons bioRxivpreprint Medium

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science (New York, N.Y.) 1068 9836639
1998 Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 441 9872318
2003 KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain : a journal of neurology 230 14534157
2000 Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current. The Journal of neuroscience : the official journal of the Society for Neuroscience 174 10684873
2006 Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains. Proceedings of the National Academy of Sciences of the United States of America 159 16735477
2015 Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. The Journal of neuroscience : the official journal of the Society for Neuroscience 156 25740509
2000 Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. The Journal of biological chemistry 141 10788442
1998 The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3. FEBS letters 124 9827540
2004 Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq. The Journal of general physiology 111 15173220
2008 Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents. Proceedings of the National Academy of Sciences of the United States of America 110 19060215
2014 Conditional deletions of epilepsy-associated KCNQ2 and KCNQ3 channels from cerebral cortex cause differential effects on neuronal excitability. The Journal of neuroscience : the official journal of the Society for Neuroscience 108 24719109
2008 Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization. The Journal of physiology 107 18483067
2003 Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium. The Journal of neuroscience : the official journal of the Society for Neuroscience 95 12832524
2001 Properties of single M-type KCNQ2/KCNQ3 potassium channels expressed in mammalian cells. The Journal of physiology 92 11432988
2002 Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 88 11784811
2000 A novel mutation of KCNQ3 (c.925T-->C) in a Japanese family with benign familial neonatal convulsions. Annals of neurology 80 10852552
2007 Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by ubiquitination. Novel role for Nedd4-2. The Journal of biological chemistry 76 17322297
2008 KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes. Neurology 75 18625963
2000 M-type KCNQ2-KCNQ3 potassium channels are modulated by the KCNE2 subunit. FEBS letters 74 11034315
2002 Antibodies and a cysteine-modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels. British journal of pharmacology 72 12466226
2016 Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations. PloS one 71 26910900
2014 A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. Epilepsia 64 25524373
2003 C-terminal interaction of KCNQ2 and KCNQ3 K+ channels. The Journal of physiology 61 12640002
2007 Developmental changes in KCNQ2 and KCNQ3 expression in human brain: possible contribution to the age-dependent etiology of benign familial neonatal convulsions. Brain & development 57 18166285
2008 Determinants within the turret and pore-loop domains of KCNQ3 K+ channels governing functional activity. Biophysical journal 50 18790849
2011 Distribution of M-channel subunits KCNQ2 and KCNQ3 in rat hippocampus. NeuroImage 48 21787867
2006 Immunohistochemical analysis of KCNQ3 potassium channels in mouse brain. Neuroscience letters 48 16513263
2013 Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders. Frontiers in genetics 43 23596459
2010 A pore residue of the KCNQ3 potassium M-channel subunit controls surface expression. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 20610766
2005 Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels. Proceedings of the National Academy of Sciences of the United States of America 39 16319223
2003 Mechanisms underlying modulation of neuronal KCNQ2/KCNQ3 potassium channels by extracellular protons. The Journal of general physiology 34 14638935
2014 DNA methylation and expression of KCNQ3 in bipolar disorder. Bipolar disorders 33 25041603
2019 A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy. Epilepsia open 32 31440727
2009 Electroconvulsive seizure thresholds and kindling acquisition rates are altered in mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions. Epilepsia 32 19453707
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
2021 Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders. Developmental neuroscience 25 33794528
2021 KCNQ variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience. Brain communications 25 34557669
2018 Kv7.3 Compound Heterozygous Variants in Early Onset Encephalopathy Reveal Additive Contribution of C-Terminal Residues to PIP2-Dependent K+ Channel Gating. Molecular neurobiology 25 29383681
2012 The Kv7.2/Kv7.3 heterotetramer assembles with a random subunit arrangement. The Journal of biological chemistry 24 22334706
2008 Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1. American journal of physiology. Cell physiology 24 18463232
2019 Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR-135a-5p to prevent the progression of epilepsy. The Kaohsiung journal of medical sciences 23 31373759
2008 Expression and localization of K channels KCNQ2 and KCNQ3 in the mammalian cochlea. Audiology & neuro-otology 23 18827480
2005 Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC). Neurogenetics 22 16235065
1997 Benign childhood epilepsy with centrotemporal spikes and electroencephalography trait are not linked to EBN1 and EBN2 of benign neonatal familial convulsions. Epilepsia 22 9579905
2004 Ionic permeation and conduction properties of neuronal KCNQ2/KCNQ3 potassium channels. Biophysical journal 20 14990473
2017 Differential Regulation of PI(4,5)P2 Sensitivity of Kv7.2 and Kv7.3 Channels by Calmodulin. Frontiers in molecular neuroscience 19 28507506
2021 CRISPR knockdown of Kcnq3 attenuates the M-current and increases excitability of NPY/AgRP neurons to alter energy balance. Molecular metabolism 18 33766732
2015 The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility. The Journal of pharmacology and experimental therapeutics 16 26087697
2008 A novel mutation of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions. Epilepsy research 16 18249525
2008 Altered KCNQ3 potassium channel function caused by the W309R pore-helix mutation found in human epilepsy. The Journal of membrane biology 15 18425618
2016 Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures. Molecular syndromology 14 27781029
2003 Genetic association analysis of KCNQ3 and juvenile myoclonic epilepsy in a South Indian population. Human genetics 14 12928862
2020 Neurofascin and Kv7.3 are delivered to somatic and axon terminal surface membranes en route to the axon initial segment. eLife 13 32903174
2016 M-currents (Kv7.2-7.3/KCNQ2-KCNQ3) Are Responsible for Dysfunctional Autonomic Control in Hypertensive Rats. Frontiers in physiology 13 27965589
2012 Benign familial neonatal convulsions caused by mutation in KCNQ3, exon 6: a European case. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 13 23146207
2009 Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions (BFNC). Epilepsy research 13 19167866
2021 The SUMO-specific protease SENP2 plays an essential role in the regulation of Kv7.2 and Kv7.3 potassium channels. The Journal of biological chemistry 12 34509475
2019 A novel mutation in KCNQ3-related benign familial neonatal epilepsy: electroclinical features and neurodevelopmental outcome. Epileptic disorders : international epilepsy journal with videotape 12 30782577
2019 Role of Kv7.2/Kv7.3 and M1 muscarinic receptors in the regulation of neuronal excitability in hiPSC-derived neurons. European journal of pharmacology 12 31238068
2016 Tannic acid activates the Kv7.4 and Kv7.3/7.5 K(+) channels expressed in HEK293 cells and reduces tension in the rat mesenteric arteries. The Journal of pharmacy and pharmacology 12 26969140
2016 The Role of KV7.3 in Regulating Osteoblast Maturation and Mineralization. International journal of molecular sciences 11 26999128
2012 Pore determinants of KCNQ3 K+ current expression. Biophysical journal 11 22713564
2003 Activation of muscarinic m5 receptors inhibits recombinant KCNQ2/KCNQ3 K+ channels expressed in HEK293T cells. European journal of pharmacology 11 12591092
2002 Histamine inhibits KCNQ2/KCNQ3 channel current via recombinant histamine H(1) receptors. Neuroscience letters 10 12147327
2024 Involvement of HDAC2-mediated kcnq2/kcnq3 genes transcription repression activated by EREG/EGFR-ERK-Runx1 signaling in bone cancer pain. Cell communication and signaling : CCS 9 39192337
2021 Place fields of single spikes in hippocampus involve Kcnq3 channel-dependent entrainment of complex spike bursts. Nature communications 9 34376649
2020 Benign familial infantile epilepsy associated with KCNQ3 mutation: a rare occurrence or an underestimated event? Epileptic disorders : international epilepsy journal with videotape 9 33337327
2018 Epilepsy-associated mutations in the voltage sensor of KCNQ3 affect voltage dependence of channel opening. The Journal of general physiology 9 30578330
2000 No evidence for association between the KCNQ3 gene and susceptibility to idiopathic generalized epilepsy. Epilepsy research 9 10996506
2020 A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate. Frontiers in physiology 8 33013448
2013 Tamoxifen inhibition of kv7.2/kv7.3 channels. PloS one 8 24086693
2012 Pore helix-S6 interactions are critical in governing current amplitudes of KCNQ3 K+ channels. Biophysical journal 6 22713565
2024 Association between Single Nucleotide Polymorphisms of PRKD1 and KCNQ3 Gene and Milk Quality Traits in Gannan Yak (Bos grunniens). Foods (Basel, Switzerland) 5 38472894
2023 SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma. Biochimica et biophysica acta. Molecular basis of disease 5 37648039
2022 Triclosan is a KCNQ3 potassium channel activator. Pflugers Archiv : European journal of physiology 5 35459955
2022 Inactivation of the Lateral Hypothalamus Attenuates Methamphetamine-Induced Conditioned Place Preference through Regulation of Kcnq3 Expression. International journal of molecular sciences 5 35806315
2020 Multiple Domains in the Kv7.3 C-Terminus Can Regulate Localization to the Axon Initial Segment. Frontiers in cellular neuroscience 5 32116557
2015 The Role of the Carboxyl Terminus Helix C-D Linker in Regulating KCNQ3 K+ Current Amplitudes by Controlling Channel Trafficking. PloS one 5 26692086
2012 Role of KCNQ2 and KCNQ3 genes in juvenile idiopathic epilepsy in Arabian foals. Veterinary journal (London, England : 1997) 5 23182620
2024 Donepezil as a new therapeutic potential in KCNQ2- and KCNQ3-related autism. Frontiers in cellular neuroscience 4 39175503
2021 Generation of an iPSC line (UNINAi001-A) from a girl with neonatal-onset epilepsy and non-syndromic intellectual disability carrying the homozygous KCNQ3 p.PHE534ILEfs*15 variant and of an iPSC line (UNINAi002-A) from a non-carrier, unaffected brother. Stem cell research 4 33799276
2020 Familial neonatal seizures caused by the Kv7.3 selectivity filter mutation T313I. Epilepsia open 4 33336127
2022 Phenotypic Spectrum in a Family Sharing a Heterozygous KCNQ3 Variant. Journal of child neurology 3 35384780
2025 DNMT3a contributes to bone cancer pain by epigenetic silencing of Kcnq2/Kcnq3 in dorsal root ganglion neurons. The journal of pain 2 40730259
2012 OS081. Novel KCNQ3/KCNE5 isoform protein and mRNA expression in first trimester human placentae. Pregnancy hypertension 2 26105295
2025 Increased KCNQ3 expression in papillary thyroid cancer promotes proliferation and migration. Cancer cell international 1 41250218
2023 Behavioral and neuro-functional consequences of eliminating the KCNQ3 GABA binding site in mice. Frontiers in molecular neuroscience 1 37305551
2023 Distinctive Amplitude-Integrated EEG Ictal Pattern and Targeted Therapy with Carbamazepine in KCNQ2 and KCNQ3 Neonatal Epilepsy: A Case Series. Neuropediatrics 1 37827512
2006 [Clinical and mutational analysis of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 16883520
2026 A de novo KCNA3 and an inherited KCNQ3 missense variant causing a developmental and epileptic encephalopathy, intellectual disability, and behavioral anomalies. Neurogenetics 0 41615502
2026 Activation of Kv7.3 channels in mPFC engram neurons suppresses methamphetamine memory retrieval by reducing excitability and glutamate release in the mPFC-NAc circuit. Cellular and molecular life sciences : CMLS 0 41746353
2026 Autism Spectrum Disorder and Atypical Epilepsy Presentation in KCNQ3 Mutations: Expansion of Phenotypic Spectrum With Neuroimaging Findings. Case reports in pediatrics 0 42255468
2025 Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3. Neuroscience bulletin 0 40095209

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