Affinage

KCND3

A-type voltage-gated potassium channel KCND3 · UniProt Q9UK17

Length
655 aa
Mass
73.5 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCND3 encodes the Kv4.3 voltage-gated potassium channel α-subunit, which generates the fast transient outward K⁺ current (Ito) in cardiomyocytes and the A-type K⁺ current (IA) in neurons, thereby shaping action potential repolarization, neuronal excitability, and subthreshold membrane potential oscillations (PMID:8831489, PMID:10772652, PMID:17314290). Kv4.3 assembles into macromolecular complexes with auxiliary subunits—KChIP1–4, Kvβ, DPPX/DPP6, DPP10, and KCNE2—that regulate its trafficking, surface expression, and gating kinetics through mechanisms including KChIP palmitoylation-dependent membrane targeting and Ca²⁺-dependent modulation of inactivation states (PMID:12135940, PMID:12006572, PMID:15890703, PMID:16738002). Channel activity is further regulated by CaMKII phosphorylation at S550, PKCα phosphorylation at isoform-specific sites, Ang II–AT1R signaling through NADPH oxidase/p38 MAPK/AUF1-mediated mRNA destabilization, NRSF-mediated epigenetic silencing, thyroid hormone receptors, and direct physical interaction with AT1R and SEMA3A; additionally, Kv4.3 sequesters inactive CaMKII at the membrane, suppressing pathological CaMKII autophosphorylation (PMID:15456698, PMID:19675305, PMID:18789946, PMID:20006971, PMID:19171649, PMID:15342638, PMID:24963029, PMID:21148163). Loss-of-function KCND3 mutations cause spinocerebellar ataxia type 19/22 (SCA19/22) through dominant-negative ER retention and impaired channel trafficking, while gain-of-function mutations cause Brugada syndrome via enhanced Ito (PMID:23280837, PMID:25854634, PMID:21349352).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 High

    Establishing KCND3 as the molecular identity of Ito resolved which gene encodes the fast transient outward K⁺ current in ventricular myocytes.

    Evidence Heterologous expression in Xenopus oocytes and cell lines reproduced biophysical and pharmacological properties of native canine/human ventricular Ito

    PMID:8831489

    Open questions at the time
    • No auxiliary subunit contributions yet defined
    • Native channel complex composition unknown
  2. 1997 High

    Discovery of alternative splicing and CNS expression expanded Kv4.3 from a cardiac channel to a broadly expressed neuronal A-type K⁺ current generator.

    Evidence RT-PCR cloning identified short and long isoforms differing by 19 amino acids; in situ hybridization mapped expression in hippocampus and multiple CNS regions; both isoforms produced functional currents

    PMID:9001401 PMID:9314834 PMID:9450548

    Open questions at the time
    • Functional consequence of the 19-aa insert unknown
    • Relative contribution to neuronal IA vs. Kv4.2 not established
  3. 2000 High

    Identification of KChIP and Kvβ auxiliary subunits as Kv4.3 partners explained how native Ito properties diverge from recombinant Kv4.3 alone and how the channel is stabilized and trafficked.

    Evidence Co-IP, co-expression electrophysiology, and protein stability assays showed KChIP2 increases current density in a Ca²⁺-dependent manner and Kvβ stabilizes Kv4.3 protein via C-terminal interaction

    PMID:11087728 PMID:12135940

    Open questions at the time
    • Full stoichiometry of the native complex not determined
    • KChIP transmural gradient mechanism not resolved
  4. 2000 High

    In vivo gain- and loss-of-function demonstrated that Kv4.3 is rate-limiting for action potential duration and QT interval, establishing its physiological necessity.

    Evidence Adenoviral Kv4.3 overexpression in guinea pig created Ito and shortened APD; dominant-negative Kv4.3-W362F in rat prolonged APD by ~30% and prolonged QT

    PMID:10772652

    Open questions at the time
    • Long-term consequences of Kv4.3 manipulation on arrhythmia susceptibility not tested
    • Compensatory remodeling of other K⁺ channels not excluded
  5. 2002 High

    Mapping the KChIP–Kv4.3 gating interface and demonstrating palmitoylation-dependent trafficking resolved how auxiliary subunits control both channel biophysics and surface expression.

    Evidence EF-hand mutagenesis separated Ca²⁺-dependent open-state from Ca²⁺-independent closed-state inactivation modulation; metabolic labeling confirmed KChIP2 palmitoylation at N-terminal cysteines is required for plasma membrane targeting of the complex

    PMID:12006572 PMID:12150935 PMID:12433945

    Open questions at the time
    • Identity of the palmitoyl transferase unknown
    • Structural basis of KChIP-Kv4.3 interaction at atomic level not yet available
  6. 2004 High

    Discovery of CaMKII phosphorylation at S550 and AT1R–Kv4.3 complex formation revealed that the channel is both a kinase substrate and a signaling scaffold.

    Evidence CaMKII dialysis slowed inactivation abolished by S550A mutation; co-IP and FRET showed AT1R physically associates with Kv4.3/KChIP2, and Ang II causes co-internalization

    PMID:15342638 PMID:15456698

    Open questions at the time
    • Whether S550 phosphorylation occurs tonically in vivo unresolved
    • Structural basis of AT1R–Kv4.3 interaction unknown
  7. 2004 High

    Kv4.3 gene transfer in pressure-overloaded hearts reversed hypertrophy by suppressing calcineurin/NFAT, placing Kv4.3 upstream of a major hypertrophic signaling pathway.

    Evidence Adenoviral Kv4.3 in aortic-banded rats restored Ito, shortened APD, and reduced calcineurin/NFATc1 expression and heart weight

    PMID:15557376

    Open questions at the time
    • Whether the anti-hypertrophic effect is purely electrophysiological or also involves CaMKII sequestration not dissected
  8. 2006 High

    Identification of DPPX and DPP10 as additional auxiliary subunits completed the reconstitution of native Ito/IA kinetics and showed that distinct accessory proteins control closed-state versus open-state inactivation.

    Evidence DPPX + KChIP2a + Kv4.3 co-expression in CHO cells reconstituted native human cardiac Ito; DPP10 truncation mutagenesis showed its transmembrane domain promotes closed-state inactivation

    PMID:15890703 PMID:16738002

    Open questions at the time
    • Relative stoichiometry of DPPX vs. DPP10 in different tissues unknown
    • Whether DPPX and KChIP compete or co-assemble simultaneously not fully resolved
  9. 2006 High

    Delineation of the Ang II–NADPH oxidase–p38 MAPK–AUF1 axis targeting Kv4.3 3ʹ-UTR explained the post-transcriptional mechanism of Ito remodeling in hypertrophy and heart failure.

    Evidence Reporter constructs with Kv4.3 3ʹ-UTR, dominant-negative Rac, NADPH oxidase inhibitors, and AUF1 overexpression/siRNA showed specificity for Kv4.3 mRNA destabilization via an AU-rich element

    PMID:16556864 PMID:18789946

    Open questions at the time
    • Whether other ARE-binding proteins besides AUF1 contribute not excluded
    • In vivo validation of AUF1 role in intact heart not performed
  10. 2009 High

    PKCα was identified as the specific conventional PKC isoform reducing Kv4.3 current, with T504 in the long-isoform 19-aa insert as the isoform-selective phosphorylation site controlling closed-state inactivation.

    Evidence PKCα siRNA and selective inhibitors blocked current reduction; T504D mutation in Kv4.3-L eliminated PMA response

    PMID:19675305 PMID:21803046

    Open questions at the time
    • Whether PKCα and CaMKII phosphorylation interact at the channel level not tested
    • In vivo relevance of T504 phosphorylation not demonstrated
  11. 2009 High

    NRSF-mediated epigenetic silencing of Kv4.3 after nerve injury explained persistent IA downregulation and neuropathic pain sensitization at a chromatin level.

    Evidence ChIP showed NRSF binding to NRSE in Kv4.3 promoter with H4 deacetylation in DRG neurons; NRSF antisense blocked Kv4.3 downregulation

    PMID:20006971

    Open questions at the time
    • Identity of the HDAC recruited by NRSF at Kv4.3 locus unknown
    • Whether this mechanism operates in cardiac remodeling not tested
  12. 2010 High

    Demonstration that Kv4.3 sequesters inactive CaMKII at the membrane established a non-conducting signaling function: Kv4.3 loss releases CaMKII, enabling pathological autophosphorylation and L-type Ca²⁺ current facilitation.

    Evidence Co-IP and FRET confirmed Kv4.3–CaMKII complex; Kv4.3 overexpression reduced basal CaMKII autophosphorylation; CaMKII release enhanced ICa,L facilitation

    PMID:21148163

    Open questions at the time
    • Structural basis of CaMKII–Kv4.3 interaction not resolved
    • Relative contribution of conducting vs. scaffolding function in disease not quantified
  13. 2012 High

    Identification of KCND3 loss-of-function mutations causing SCA19/22 via ER retention and dominant-negative suppression of wild-type channel trafficking established Kv4.3 as essential for cerebellar function.

    Evidence Whole exome sequencing in multiple families; mutant channels showed ER retention, protein instability, absent/reduced current; co-expression with WT demonstrated dominant-negative effects rescued partially by KChIP2

    PMID:23280837 PMID:23280838 PMID:25854634 PMID:31293010

    Open questions at the time
    • Which cerebellar neuron subtypes are most vulnerable not defined
    • Whether KChIP rescue is therapeutically exploitable not tested
  14. 2011 High

    KCND3 gain-of-function mutations linked to Brugada syndrome demonstrated that excessive Ito causes J-wave arrhythmias by eliminating the action potential dome.

    Evidence L450F and G600R mutations co-expressed with KChIP2 in HEK293 cells showed 50–146% increased peak current; Luo-Rudy simulation modeled dome loss

    PMID:21349352

    Open questions at the time
    • Patient-derived cardiomyocyte validation not performed
    • Whether other Ito-related genes modify penetrance not examined
  15. 2014 High

    SEMA3A was identified as a novel direct Kv4.3 inhibitor acting through the toxin-binding domain, revealing a non-canonical extracellular regulation of Ito independent of surface expression changes.

    Evidence Co-IP confirmed physical Kv4.3–SEMA3A interaction; domain mutagenesis disrupted inhibition; current reduction without surface expression change in HEK293 and hiPSC-cardiomyocytes

    PMID:24963029

    Open questions at the time
    • Whether endogenous SEMA3A levels regulate cardiac Ito in vivo unknown
    • Binding affinity and stoichiometry not quantified
  16. 2020 High

    Combinatorial assembly of distinct KChIP and DPP isoforms with Kv4.3 was shown to determine cell-type-specific firing phenotypes in hippocampal interneurons, establishing auxiliary subunit identity as the primary determinant of functional diversity.

    Evidence Patch clamp, immunohistochemistry, and transcriptomics in CCK⁺ interneurons showed KChIP1 vs. KChIP4e/DPP6S produce distinct firing despite comparable Kv4.3 levels

    PMID:32490811

    Open questions at the time
    • Whether auxiliary subunit composition changes dynamically with activity not known
    • Contribution of Kv4.2 heteromers not fully excluded
  17. 2021 High

    Kv4.3 downregulation in trigeminal nociceptors was shown to underlie cold hypersensitivity after nerve injury, and pharmacological Kv4.3 potentiation reversed cold allodynia, validating Kv4.3 as a pain target.

    Evidence Immunostaining and patch clamp in TG neurons after ION-CCI; phrixotoxin-2 recapitulated allodynia; Kv4.3 potentiation alleviated it behaviorally

    PMID:33472822

    Open questions at the time
    • Identity of the Kv4.3 potentiator drug and its selectivity profile not fully characterized
    • Whether central Kv4.3 changes also contribute not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • High-resolution structures of intact Kv4.3 channel complexes with auxiliary subunits, the precise stoichiometry and spatial organization of the native macromolecular complex, and the relative contributions of Kv4.3's conducting versus CaMKII-scaffolding functions to cardiac and neuronal disease remain to be determined.
  • No cryo-EM or crystal structure of the full Kv4.3–KChIP–DPP ternary complex
  • Relative pathogenic contribution of ion conduction loss vs. CaMKII desequestration not dissected in disease models
  • Therapeutic potential of auxiliary-subunit-targeted interventions for SCA19/22 untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4
Partners
AGTR1DPP10DPP6KCNAB2KCNE2KCNIP1KCNIP2KCNIP3
Complex memberships
Kv4.3/AT1R/KChIP2 signaling complexKv4.3/CaMKII scaffolding complexKv4.3/KChIP2/DPPX ternary channel complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Kv4.3 encodes a rapidly inactivating A-type K+ current (transient outward current, Ito) when expressed in heterologous systems, with biophysical and pharmacological properties matching native canine and human ventricular Ito. Heterologous expression and electrophysiology (whole-cell patch clamp) in Xenopus oocytes and cell lines Circulation research High 8831489
1997 Kv4.3 exists as alternatively spliced isoforms (short and long, differing by a 19-amino acid insertion in the C-terminal intracellular region); the long isoform is predominant in rat heart and lung, while both isoforms produce functional A-type K+ currents. RT-PCR cloning and functional expression in HEK293 cells with whole-cell patch clamp FEBS letters High 9314834 9450548
1997 Kv4.3 is expressed in rat hippocampus and multiple CNS regions and produces an A-type K+ current when expressed in Xenopus oocytes, consistent with a role in controlling subthreshold A-currents and neuronal excitability. cDNA cloning, functional expression in Xenopus oocytes, in situ hybridization FEBS letters High 9001401
2000 KChIP2 auxiliary subunits associate with Kv4.3, increase current density, slow current decay in a Ca2+-dependent manner, and hasten recovery from inactivation; a steep transmural gradient of KChIP2 mRNA (but not protein) exists in human/canine ventricle. Heterologous co-expression, whole-cell patch clamp, kinetic RT-PCR, Western blot, immunocytochemistry Circulation High 12135940
2000 Kv4.3 associates with Kvβ2 subunits in brain; Kvβ1 or Kvβ2 co-expression increases Kv4.3 current density and protein expression (by stabilizing the protein) without affecting channel gating; this interaction requires the C-terminus but not N-terminus of Kv4.3. Co-immunoprecipitation, transfection/expression in heterologous cells, whole-cell patch clamp, protein stability assays The Journal of biological chemistry High 11087728
2000 Nicotine directly blocks Kv4.3 channels (IC50 ~40 nM) by both tonic and use-dependent block, reducing single-channel conductance, open probability, and open time, without altering activation kinetics; this effect is receptor-independent. Whole-cell and single-channel patch clamp in Xenopus oocytes and canine ventricular myocytes Circulation High 10973847
2000 In vivo overexpression of Kv4.3 by adenoviral gene transfer in guinea pig myocytes produces robust Ito, depresses the plateau potential, and abbreviates action potential duration; dominant-negative Kv4.3-W362F suppresses Ito in rats, elevates plateau height, prolongs APD by ~30%, and prolongs QT interval. In vivo adenoviral gene transfer, whole-cell patch clamp, surface ECG recordings The Journal of clinical investigation High 10772652
2001 Angiotensin II (Ang II) downregulates Kv4.3 mRNA by destabilizing the transcript (via mRNA half-life reduction), while phenylephrine (PE) downregulates Kv4.3 mRNA via transcriptional repression of the Kv4.3 promoter; the two pathways act independently. RNase protection assays, mRNA turnover measurements, Kv4.3 promoter-reporter assays in neonatal rat cardiac myocytes, immunoblots Circulation research High 11249870
2002 KChIP auxiliary subunits modulate Kv4.3 inactivation and recovery via distinct structural domains: the EF-hand modulates effects on inactivation but not recovery; Ca2+-independent effects on recovery are mediated through a short non-EF-hand stretch; closed-state inactivation is Ca2+-independent while open-state inactivation is Ca2+-dependent. Cloning of minimal KChIP2d isoform, heterologous expression in Xenopus oocytes, whole-cell patch clamp with mutagenesis The Journal of physiology High 12433945
2002 Palmitoylation of KChIP2 isoforms at N-terminal cysteine residues is required for plasma membrane localization of KChIP2 and for efficient trafficking and increased surface expression of associated Kv4.3 channels; metabolic labeling confirmed palmitoylation at these cysteines. Metabolic labeling (palmitoylation assay), site-directed mutagenesis, confocal microscopy, whole-cell patch clamp The Journal of biological chemistry High 12006572
2002 KChIP2b modulates Kv4.3 gating via inner pore structure; mutation of inner pore residues V399I/V401I reveals that the inner pore is important for the modulatory effect of KChIP2b on inactivation kinetics; KChIP2b increases rate of recovery from inactivation of both WT and mutant channels. Site-directed mutagenesis, heterologous expression, whole-cell patch clamp Biochemical and biophysical research communications Medium 12150935
2002 Kv4.3 exhibits a C-type (external pore collapse) inactivation mechanism; removal of external K+ destabilizes the conducting state by collapsing the selectivity filter pore, consistent with C-type inactivation. Whole-cell voltage clamp, manipulation of external K+ concentration, biophysical analysis The Journal of membrane biology Medium 12172648
2004 CaMKII directly phosphorylates Kv4.3 at residue S550A in the C-terminal region, slowing inactivation and accelerating recovery from inactivation; mutation S550A abolishes these CaMKII effects, establishing S550 as the CaMKII target site. Site-directed mutagenesis, intracellular dialysis of autophosphorylated CaMKII, whole-cell patch clamp American journal of physiology. Cell physiology High 15456698
2004 KChIP2 isoforms modulate Kv4.3 gating by accelerating recovery from inactivation, slowing closed-state inactivation, and promoting open-state inactivation; Ca2+-dependent effects operate selectively through open-state inactivation, while closed-state inactivation transitions are Ca2+-independent. Xenopus oocyte expression, whole-cell patch clamp with detailed kinetic modeling The Journal of physiology High 14724186
2004 Angiotensin receptor type 1 (AT1R) forms a physical complex with Kv4.3 and KChIP2 in canine ventricular cells and HEK293 cells; Ang II treatment causes co-internalization of Kv4.3 with AT1R and shifts the activation voltage threshold of remaining surface Kv4.3 channels to more positive values. Co-immunoprecipitation, FRET, fluorescence co-localization (ECFP/EYFP-tagged proteins), whole-cell patch clamp The Journal of biological chemistry High 15342638
2004 In vivo Kv4.3 gene transfer in rats with aortic stenosis restores Ito density, shortens action potential duration, and abrogates the hypertrophic response by reducing calcineurin and NFATc1 expression, placing Kv4.3 upstream of the calcineurin/NFAT hypertrophic pathway. In vivo adenoviral gene transfer, whole-cell patch clamp, Western blot, heart weight measurements Circulation High 15557376
2005 DPPX (DPP6) acts as an additional beta-subunit of Kv4.3 in human heart; co-expression of DPPX with Kv4.3 and KChIP2a reconstitutes native human cardiac Ito kinetics (faster inactivation, more negative half-inactivation, delayed recovery compared to Kv4.3+KChIP2a alone). Quantitative RT-PCR, Western blot with DPPX-specific antibody, co-expression in CHO cells, whole-cell patch clamp The Journal of physiology High 15890703
2006 Ang II and mechanical stretch activate NADPH oxidase (via AT1 receptors, superoxide, and ASK1-p38 kinase signaling) to specifically destabilize Kv4.3 channel mRNA through sequences in the 3'-UTR, while Kv4.2 and Kv1.5 3'-UTRs are insensitive. Reporter construct assays with Kv4.3 3'-UTR, dominant-negative Rac, NADPH oxidase inhibitors, SOD/catalase overexpression, kinase inhibitors in neonatal rat cardiac myocytes Circulation research High 16556864
2006 DPP10 modulates Kv4.3 inactivation by causing negative shifts in steady-state activation and inactivation and promoting closed-state inactivation, through its transmembrane and short cytoplasmic domain; DPP10 and KChIP2b have different primary effects (closed-state vs. open-state inactivation respectively). Heterologous co-expression, whole-cell patch clamp, truncation mutagenesis of DPP10 American journal of physiology. Cell physiology High 16738002
2006 CaMKII co-immunoprecipitates with Kv4.3 (but not Kv4.2) in rat cardiac myocytes without prior Ca2+ elevation; CaMKII phosphorylates Kv4.3 at baseline, slowing its inactivation; Kv4.3 acts as a molecular scaffold concentrating CaMKII at the membrane, enabling Ca2+-dependent modulation of associated Kv4.2 channels. Co-immunoprecipitation, Western blot with phospho-specific antibodies, whole-cell patch clamp in myocytes and HEK cells American journal of physiology. Heart and circulatory physiology High 16648177
2007 Kv4.3 mediates A-type K+ currents in CA1 LM/RAD hippocampal interneurons and is required for subthreshold membrane potential oscillations; siRNA knockdown of Kv4.3 selectively impairs A-type K+ currents and MPOs in these interneurons. siRNA knockdown, whole-cell patch clamp, immunolabeling in hippocampal slices The Journal of neuroscience High 17314290
2008 AUF1 (ARE/poly-U binding/degradation factor 1) is upregulated by Ang II via AT1R-NADPH oxidase-p38 MAPK signaling; AUF1 binds to an AU-rich element (ARE) in the Kv4.3 3'-UTR to destabilize the channel mRNA; overexpression of AUF1 mimics and occludes the Ang II effect, and siRNA against AUF1 blocks it. Deletion and mutagenesis of 3'-UTR ARE, AUF1 overexpression and siRNA knockdown, RNA pulldown assays, reporter assays Journal of molecular and cellular cardiology High 18789946
2008 KCNE2 (MiRP1) co-assembles with Kv4.3 and reduces peak current density, slows inactivation, and shifts steady-state inactivation positively, making Kv4.3 more like native cardiac Ito; KCNE2 variants M54T and I57T cause gain-of-function by increasing current density. Heterologous co-expression in cell lines, whole-cell patch clamp Heart rhythm Medium 20042375
2008 KChIP4a crystal structure at 3.0 Å resolution shows distinct N-terminal alpha-helices; competitive binding of the Kv4.3 N-terminal peptide to the hydrophobic groove of KChIP4a displaces the KChIP4a N-terminus, which acts as a slow inactivation gate suppressing Kv4.3 inactivation. X-ray crystallography, biochemical binding assays, electrophysiology, N-terminal peptide fusion experiments The Journal of biological chemistry High 19109250
2009 Nerve injury causes NRSF to bind the NRSE element in the Kv4.3 gene promoter in dorsal root ganglion neurons, leading to deacetylation of histone H4 at the NRSE (epigenetic silencing) and long-lasting Kv4.3 mRNA downregulation; NRSF antisense knockdown blocks this effect. ChIP assay for NRSF binding and histone acetylation, RT-PCR, antisense knockdown in vivo Neuroscience High 20006971
2009 Alanine scanning of the Kv4.3 S3b region identifies L275 and V276 as critical residues for interaction with HpTx2 (an ICK gating modifier toxin); KChIP2b stabilizes the closed state of Kv4.3, increasing HpTx2 affinity; the S3b hydrophobic character is the primary determinant of toxin binding. Site-directed mutagenesis, functional expression, concentration-response electrophysiology Molecular pharmacology Medium 19357248
2009 Thyroid hormone receptor alpha1 (TRα1) activates KCND3 transcription via a response element at -1651 bp, while TRβ1 suppresses KCND3 transcription via a different response element at -73 bp; both effects are ligand-dependent; TRα1 increases Ito and TRβ1 reduces Ito in cardiomyocytes. Adenoviral gene transfer, promoter-reporter constructs, mutagenesis of TR binding sites, whole-cell patch clamp in rat cardiomyocytes The Journal of physiology High 19171649
2009 Ang II downregulates Kv4.3 mRNA and protein in RVLM neurons via AT1R-ROS-p38 MAPK signaling, decreasing A-type K+ current and increasing neuronal excitability; this mechanism contributes to sympathoexcitation in chronic heart failure. GeneChip screening, RT-PCR, Western blot, whole-cell patch clamp in CATH.a neurons, microinjection in intact animals, kinase inhibitors American journal of physiology. Heart and circulatory physiology Medium 20044444
2010 Kv4.3 and inactive CaMKII form a complex at the cardiomyocyte membrane (shown by co-IP and FRET); Kv4.3 blocks CaMKII activation by binding to the calmodulin binding sites; dissociation of CaMKII from the Kv4.3-CaMKII complex releases these sites and leads to CaMKII autophosphorylation and L-type Ca2+ current facilitation. Kv4.3 overexpression reduces basal CaMKII autophosphorylation. Co-immunoprecipitation, FRET, L-type Ca2+ current recordings, Ca2+ chelation (BAPTA vs. EGTA), Kv4.3 overexpression in myocytes European heart journal High 21148163
2010 Kv4.2, Kv4.3, and Kv1.4 alpha-subunits encode three distinct, separable components of the macroscopic IA current in mouse cortical pyramidal neurons, as determined by targeted gene deletion. Genetic knockout (Kv4.2-/-, Kv4.3-/-, double and compound knockouts), whole-cell patch clamp with pharmacological blockers The Journal of neuroscience High 20371829
2011 PKCα is the primary isoenzyme mediating PKC-dependent reduction of Kv4.3 current; conventional PKC activation reduces Kv4.3 current in a PKCα-dependent manner (blocked by PKCα siRNA and HBDDE), while novel PKC isoforms have no significant effect. Xenopus oocyte expression with double electrode voltage clamp, siRNA knockdown of PKC isoforms, pharmacological activators/inhibitors, patch clamp in rat cardiomyocytes Journal of molecular and cellular cardiology High 21803046
2011 Two KCND3 gain-of-function mutations (L450F and G600R) associated with Brugada syndrome increase peak Ito current density by 146% and 50%, respectively, when co-expressed with KChIP2 in HEK293 cells; simulation modeling shows that increased Ito causes loss of the action potential dome. Site-directed mutagenesis, co-expression with KChIP2, whole-cell patch clamp in HEK293 cells, Luo-Rudy AP simulation Heart rhythm High 21349352
2012 KCND3 loss-of-function mutations causing SCA19/22 (T352P, M373I, S390N, F227del, G345V, V338E, T377M) result in ER retention, protein instability, and absent or reduced K+ channel current; KChIP2 can rescue membrane localization and stability of some mutants but does not fully restore channel function. Whole exome sequencing, site-directed mutagenesis, heterologous expression in HeLa cells, immunofluorescence, patch-clamp electrophysiology, autopsy immunohistochemistry Annals of neurology High 23280837 23280838
2012 Large T-antigen upregulates Kv4.3 expression through increasing the transcription factor Sp1; Sp1 decoy oligonucleotides reduce Kv4.3 expression; Kv4.3 inhibition (via 4-AP or siRNA) induces cell apoptosis and necrosis through CaMKII activation (prevented by KN-93). Sp1 decoy oligonucleotides, Sp1 overexpression vector, Kv4.3 siRNA, pharmacological blockers, cell death assays, KN-93 rescue in HEK293/HEK293T cells The Biochemical journal Medium 22023388
2009 Closed-state inactivation (CSI) of Kv4.3 isoforms is differentially regulated by PKC: PMA reduces CSI in Kv4.3-S but increases CSI in Kv4.3-L; mutation of T504 (a PKC site unique to the 19-amino acid insert of Kv4.3-L) to aspartate eliminates the PMA response, identifying T504 as the isoform-specific PKC phosphorylation site. Site-directed mutagenesis, Xenopus oocyte expression with double electrode voltage clamp, PMA and purified PKC treatment American journal of physiology. Cell physiology High 19675305
2014 NS5806 binds to a hydrophobic site on the C-terminus of KChIP3 in a Ca2+-dependent manner (Kd 2-5 μM), increasing the affinity between KChIP3 and the N-terminus of Kv4.3 and decreasing the rate of their dissociation; Tyr-174 and Phe-218 on KChIP3 are required for this drug-induced enhancement. Fluorescence spectroscopy, isothermal titration calorimetry, docking simulations, site-directed mutagenesis The Journal of biological chemistry High 25228688
2014 SEMA3A (semaphorin 3A) selectively inhibits Kv4.3 (but not Nav1.5, Cav1.2, or Kv4.2) by directly binding to Kv4.3, reducing peak current density without altering surface protein expression; co-immunoprecipitation confirms physical interaction; disruption of a putative toxin-binding domain on Kv4.3 disrupts SEMA3A inhibition. Co-immunoprecipitation, whole-cell patch clamp in HEK293 cells and hiPSC-derived cardiomyocytes, domain disruption mutagenesis, perfusion experiments Circulation research High 24963029
2015 SCA19/22-mutant Kv4.3 subunits exert dominant negative effects on wild-type Kv4.3 trafficking and surface expression in the absence of KChIP2; KChIP2 co-expression rescues this dominant negative effect on trafficking; all tested mutants either suppress WT Kv4.3 current amplitude or alter gating in a dominant manner. Co-expression of mutant and WT Kv4.3, immunofluorescence for localization, whole-cell patch clamp Cellular and molecular life sciences High 25854634
2015 A de novo KCND3 mutation (p.Arg293_Phe295dup) duplicating the RVF motif in the voltage-sensor domain causes a severe positive shift in voltage-dependence of gating and markedly reduced channel opening, correlating with a severe SCA19/22 phenotype with intellectual disability, epilepsy, and ataxia. Whole exome sequencing, immunocytochemistry, immunoblotting, patch clamp assays BMC medical genetics Medium 26189493
2019 Novel SCA19/22-associated KCND3 mutations (C317Y, P375S, V338E, T377M) cause loss-of-function with enhanced protein degradation and defective membrane trafficking; co-expression of mutant subunits with WT KV4.3 demonstrates dominant-negative effects on protein biosynthesis and voltage-dependent gating. Targeted NGS, heterologous expression, electrophysiology, Western blot for protein stability, immunofluorescence for trafficking, co-expression with WT channel Human mutation High 31293010
2008 KChIP1 co-expression modulates Kv4.3 A-type K+ currents in HEK293 cells (faster recovery, leftward activation shift, faster rise time, slower decay); in hippocampal LM/RAD interneurons, KChIP1 siRNA knockdown slows recovery from inactivation and increases firing frequency during sustained depolarization, indicating KChIP1 regulates Kv4.3-based interneuron excitability. HEK293 co-expression electrophysiology, siRNA knockdown in hippocampal slice cultures, whole-cell patch clamp Neuroscience High 21129448
2020 Alternative isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S) determine distinct firing phenotypes of CCK+ hippocampal interneurons by differentially modulating Kv4.3-mediated low-voltage-activated K+ currents, despite comparable Kv4.3 expression levels in both cell types. Patch clamp electrophysiology in hippocampal slices, immunohistochemistry, transcriptomic profiling, pharmacology eLife High 32490811
2021 Downregulation of Kv4.3 in nociceptive trigeminal ganglion neurons after infraorbital nerve injury reduces IA currents and underlies cold hypersensitivity; pharmacological inhibition of Kv4.3 (phrixotoxin-2) recapitulates cold allodynia, while pharmacological potentiation of Kv4.3 alleviates it in ION-CCI rats. Immunostaining, patch-clamp of acutely dissociated TG neurons, orofacial operant behavioral testing, pharmacological manipulation in vivo The Journal of neuroscience High 33472822
2021 miR-27a-3p targets the 3'-UTR of Hoxa10, reducing Hoxa10 protein expression; Hoxa10 positively regulates Kv4.3 expression; miR-27a-3p inhibition or Hoxa10 overexpression alleviates Ang II-induced cardiomyocyte hypertrophy and restores Kv4.3 levels, establishing a miR-27a-3p/Hoxa10/Kv4.3 regulatory axis. Luciferase reporter assay, miRNA inhibitor transfection, Hoxa10 overexpression, Western blot, patch clamp Frontiers in pharmacology Medium 34248630

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circulation research 388 8831489
1998 Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 321 9760292
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