Affinage

KCNA4

Potassium voltage-gated channel subfamily A member 4 · UniProt P22459

Length
653 aa
Mass
73.3 kDa
Annotated
2026-06-10
94 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNA4 encodes Kv1.4, a voltage-gated, rapidly-inactivating A-type potassium channel that shapes membrane excitability in heart and nervous system by generating a slow transient outward current (Ito,s in cardiomyocytes) and A-type currents (IA) in neurons (PMID:10884375, PMID:37158881). Its hallmark fast N-type inactivation is conferred by a proximal N-terminal ball domain, where an electrostatic interaction between positively and negatively charged segments tunes inactivation rate; a single inactivating subunit suffices to inactivate a heteromultimer (PMID:8661510, PMID:20674541, PMID:8788936). Removal of this N-terminal domain unmasks a slower C-type inactivation coupled to activation and governed by pore residues—extracellular H508 and K532/K531 and the S6 residue V561—and by permeant K+ ions, with extracellular acidosis enhancing C-type inactivation through protonation of H508 (PMID:8788936, PMID:10896716, PMID:12388308). Channel gating is dynamically regulated: CaMKII and PKA (at Ser229 in the T1 domain) phosphorylation, redox modification of N-terminal cysteines, fatty acids, and accessory subunits (Kvbeta1.1/1.2/2/3, DPP10) and synaptotagmin I all modulate inactivation and recovery kinetics (PMID:9133364, PMID:16000151, PMID:8584439, PMID:14724761, PMID:7631872, PMID:9763623, PMID:16738002, PMID:24423395). Surface expression and stability depend on N-glycosylation, a pore trafficking determinant interdependent with the C-terminal VXXSL motif, PKC/AMPK signaling, and clustering by PSD-95, which suppresses internalization and recruits Kv1.4 into palmitoylation-dependent lipid rafts via its C-terminal PDZ-binding motif (PMID:14688283, PMID:12901718, PMID:29168928, PMID:10625685, PMID:14559911). Kv1.4 localizes presynaptically at excitatory hippocampal synapses and is required for hippocampal LTP, and its loss in mice eliminates Ito,s and predisposes to arrhythmias including ventricular tachycardia (PMID:9437018, PMID:9844011, PMID:10884375). In humans, loss-of-function KCNA4 missense variants (p.Arg89Gln; p.Val558L in the S6 hinge) cause severe channel dysfunction associated with developmental epileptic encephalopathy (PMID:27582084, PMID:40472070).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Establishing the two-component inactivation architecture of Kv1.4 separated the fast N-type 'ball' mechanism from a slower intrinsic C-type process and showed C-type inactivation sets the overall recovery rate.

    Evidence N-terminal deletion and S4 mutagenesis with two-electrode voltage clamp in Xenopus oocytes

    PMID:8788936

    Open questions at the time
    • Structural basis of C-type inactivation not resolved
    • Coupling to activation defined functionally, not structurally
  2. 1996 Medium

    Identifying the proximal N-terminal ball domain and the redox sensitivity of N-terminal cysteines defined the molecular determinant of fast inactivation and its chemical regulation.

    Evidence Tandem Kv1.4-Kv1.5 fusion/deletion constructs and cysteine-modifying reagents with voltage/patch clamp

    PMID:8584439 PMID:8661510

    Open questions at the time
    • Stoichiometry of redox effect on tetramer not quantified
    • Physiological oxidant in vivo not identified
  3. 1997 High

    Phosphoregulation made Kv1.4 inactivation Ca2+-responsive, linking CaMKII/calcineurin signaling to channel gating and use-dependent availability.

    Evidence In vitro kinase/phosphatase assays plus oocyte electrophysiology and mutagenesis

    PMID:9133364

    Open questions at the time
    • Precise N-terminal phosphoresidue partially defined
    • Native neuronal/cardiac relevance not directly tested here
  4. 1997 Medium

    Beta-subunit and dominant-negative truncation studies established that Kv1.4 assembles into heteromultimers whose assembly state controls both gating and ER export.

    Evidence Co-expression electrophysiology and double immunoprecipitation/fractionation in GH3 cells

    PMID:9334228 PMID:9359902

    Open questions at the time
    • Native subunit composition not enumerated
    • Trafficking checkpoint mechanism not molecularly defined
  5. 1998 Medium

    Defining the PSD-95 palmitoylation-PDZ axis and presynaptic localization placed Kv1.4 within scaffolded synaptic membrane microdomains and a functional LTP role.

    Evidence Palmitoylation labeling, co-IP, immuno-EM localization, and hippocampal antisense knockdown with slice electrophysiology

    PMID:9437018 PMID:9459448 PMID:9763623 PMID:9844011

    Open questions at the time
    • Direct presynaptic current contribution not isolated
    • Causal chain from channel loss to LTP deficit not fully resolved
  6. 2000 High

    Demonstrating PSD-95 clustering suppresses internalization and that acidosis enhances C-type inactivation via H508 connected scaffolding and pore chemistry to channel surface stability and pathophysiological modulation.

    Evidence Biotinylation internalization assays in HEK293 and site-directed mutagenesis (H508Q, K532Y) with oocyte voltage clamp

    PMID:10625685 PMID:10896716

    Open questions at the time
    • Internalization endocytic machinery not identified
    • In vivo significance of acidosis effect not tested
  7. 2000 High

    Knockout and transgenic mouse models proved Kv1.4 is the molecular basis of cardiac Ito,s and that its loss combined with Ito,f deficiency produces lethal arrhythmias.

    Evidence Gene knockout/transgenic mice with in vivo ECG and myocyte patch clamp

    PMID:10884375

    Open questions at the time
    • Compensatory channel remodeling not fully mapped
    • Human cardiac translation indirect
  8. 2003 Medium

    Defining glycosylation, pore-region, and VXXSL trafficking determinants, plus lipid-raft recruitment, established the structural code controlling Kv1.4 surface expression.

    Evidence Chimeric and glycosylation mutagenesis, surface expression assays, and lipid raft fractionation in heterologous cells

    PMID:12901718 PMID:14559911 PMID:14688283

    Open questions at the time
    • Trafficking machinery and chaperones not identified
    • Interdependence mechanism between pore and C-terminus not structurally resolved
  9. 2005 Medium

    Identifying PKA phosphorylation of T1-domain Ser229 driven by NMDA-receptor Ca2+ influx linked synaptic activity to Kv1.4 current density in native neurons.

    Evidence In vitro kinase assay, phospho-specific Western blot, and S229A mutagenesis in cortical neurons

    PMID:16000151

    Open questions at the time
    • Mechanism by which Ser229 phosphorylation alters current density unclear
    • Single lab
  10. 2011 High

    Programmed heterotetramer studies showed positional, subunit-adjacency requirements for inactivation modulation, refining the structural logic of heteromeric Kv1.4 channels.

    Evidence Single-chain concatenated heterotetramers in HEK293 with NIP mutagenesis and whole-cell electrophysiology

    PMID:16738002 PMID:20674541 PMID:21352098

    Open questions at the time
    • Native tetramer subunit arrangement unknown
    • Generality across other Kv1.x partners not established
  11. 2014 Medium

    Identifying direct synaptotagmin I binding to the Kv1.4 N-terminus added a Ca2+-dependent presynaptic regulator of fast inactivation.

    Evidence Co-IP and whole-cell patch clamp with N-terminal mutagenesis in HEK293T

    PMID:24423395

    Open questions at the time
    • Single Co-IP system without reciprocal in vivo validation
    • Physiological synaptic consequence not measured
  12. 2021 Medium

    Transcriptional and post-transcriptional regulators (Nup50, miR-448) and trafficking kinases (PKC, AMPK) were shown to set Kv1.4 abundance and current, expanding regulation beyond gating.

    Evidence ChIP/reporter assays, RNA pull-down with binding-site mutation, and kinase activation with imaging/electrophysiology

    PMID:29168928 PMID:34409458 PMID:36693615

    Open questions at the time
    • Disease contexts inferred (ischemia) not fully tested in vivo
    • Integration of these inputs with channel function incomplete
  13. 2025 Medium

    Human genetic and functional studies established KCNA4 loss-of-function variants as causes of developmental epileptic encephalopathy, providing direct disease relevance.

    Evidence Trio whole-exome sequencing with cell-based patch clamp and trafficking assays (p.Arg89Gln, p.Val558L)

    PMID:27582084 PMID:40472070

    Open questions at the time
    • Genotype-phenotype spectrum not delineated
    • Mechanism linking channel loss to encephalopathy circuit defects unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse regulatory inputs—phosphorylation, redox, lipid, scaffolding, accessory subunits, and transcriptional control—are integrated in native presynaptic and cardiac contexts, and how loss-of-function produces specific human neurodevelopmental phenotypes, remains unresolved.
  • No structural model of full regulated channel complex
  • Native cell-type-specific regulatory hierarchy undefined
  • Disease mechanism at circuit level uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-397014 Muscle contraction 1
Partners
ACTN2DLG1DLG2DPP10KCNA1KCNAB1KCNAB2SYT1
Complex memberships
Kv1.4-Kv1.1 heteromeric channelKv1.4/Kvbeta heteromultimeric channelPSD-95/Kv1.4 scaffold complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CaMKII phosphorylates an N-terminal residue of Kv1.4, slowing inactivation gating and accelerating recovery from N-type inactivated states; dephosphorylation by the calcineurin/inhibitor-1 cascade induces fast inactivation with increased tendency for cumulative inactivation during repetitive stimulation, rendering Kv1.4 inactivation Ca2+-sensitive. In vitro kinase/phosphatase assays, electrophysiology (Xenopus oocyte expression), mutagenesis The Journal of Neuroscience High 9133364
1995 Deletion of the N-terminal domain (residues 2–146) of Kv1.4 removes fast N-type inactivation and reveals a slow C-type inactivation process; C-type inactivation is coupled to activation and governs the overall rate of recovery from inactivation in both full-length and N-terminal deleted channels. Two-electrode voltage clamp in Xenopus oocytes, N-terminal deletion mutagenesis, S4 voltage sensor mutation (R454Q) The Journal of Physiology High 8788936
1998 PSD-95 is palmitoylated on N-terminal cysteines 3 and 5, and palmitoylated PSD-95 partitions exclusively with cell membranes; palmitoylation-deficient PSD-95 mutants fail to participate in PDZ-Kv1.4 ion channel interactions in vivo. Metabolic palmitoylation labeling, mutagenesis, co-immunoprecipitation, cell-surface distribution assays Neuron High 9459448
2000 PSD-95 clustering completely suppresses Kv1.4 internalization in HEK293 cells; a palmitoylation-competent but clustering-deficient PSD-95 mutant (C35S) instead enhances the rate of Kv1.4 internalization, demonstrating that PSD-95-mediated clustering—not mere binding—stabilizes Kv1.4 at the cell surface. Cell-surface biotinylation internalization assay, immunochemistry, whole-cell electrophysiology, GFP-tagged Kv1.4 imaging The Journal of Biological Chemistry High 10625685
2003 PSD-95 palmitoylation recruits Kv1.4 (but not Kv4.2) into lipid rafts via the Kv1.4 C-terminal PDZ-binding motif; deleting this motif or substituting a palmitoylation-deficient PSD-95 eliminates raft recruitment. Lipid raft fractionation, raft patching/immunostaining, co-expression in heterologous system, deletion mutagenesis The Journal of Biological Chemistry High 14559911
1999 N-terminal cysteines 3 and 5 of PSD-95 are required for PSD-95 multimerization and formation of a ternary complex with Kv1.4 and Fasciclin II, but are dispensable for membrane association and binary Kv1.4 binding; multimerization is required for simultaneous binding of multiple membrane protein ligands. Co-immunoprecipitation, cell clustering assays, mutagenesis The Journal of Biological Chemistry Medium 9867876
2001 PDZ2 of PSD-95 (highest affinity for Kv1.4) is the primary domain required for efficient Kv1.4 clustering; functional PDZ2 must occupy the second position in the full-length protein, as inversion of PDZ1-PDZ2 order abolishes clustering activity. PDZ domain missense/deletion mutagenesis, co-expression clustering assay in COS-1 cells The Journal of Biological Chemistry Medium 11723117
2003 N-glycosylation of Kv1.4 (attached at the S1-S2 linker) promotes protein stability and cell-surface expression; preventing glycosylation decreases protein stability and causes intracellular retention, with effects contingent on a pore region trafficking determinant that can be transferred to chimeric Kv1.1. N-glycosylation mutagenesis, cell-surface expression assays, chimeric channel construction in transfected cells The Journal of Biological Chemistry Medium 14688283
2003 Kv1.4 cell-surface trafficking requires interdependence between a pore region determinant and the cytoplasmic C-terminal VXXSL motif; removal of VXXSL only inhibits surface expression when the Kv1.4 pore (specifically a threonine in the deep pore) is present, not when replaced by the Kv1.1 pore. Chimeric channel mutagenesis, cell-surface expression assays in transfected cells The Biochemical Journal Medium 12901718
2001 The N-terminus of Kv1.4 interacts with the spectrin repeats of alpha-actinin-2 (but Kv1.1, 1.2, 1.3 do not); the Kv1.4/Kv1.5 binding region in alpha-actinin-2 lies within its internal spectrin repeats, and calmodulin has no effect on this interaction. Yeast two-hybrid, in vitro binding (pull-down) assays, deletion mutagenesis FEBS Letters Medium 11389904
2000 Acidosis inhibits Kv1.4 during repetitive pulsing by protonation of extracellular histidine H508, which enhances C-type inactivation and slows recovery from N-type inactivation; deletion of both N-terminal inactivation ball domains greatly reduces the acidosis effect, and raising extracellular K+ or the K532Y mutation abolishes it. Two-electrode voltage clamp in Xenopus oocytes, site-directed mutagenesis (H508Q, K532Y), extracellular K+ manipulation The Journal of Physiology High 10896716
2002 C-type inactivation of Kv1.4 is regulated by extracellular K+ (via pore mouth and intracellular K+ binding sites), intracellular K+ concentration, extracellular pH via H508 in the S5-H5 linker, and an extracellular K532Y mutation; an intracellular V561A mutation in S6 alters C-type inactivation and inverts its relationship with extracellular K+, suggesting transmembrane communication between intracellular and extracellular pore regions. Two-electrode voltage clamp in Xenopus oocytes, N-terminal deletion, site-directed mutagenesis (H508, K532, V561A), ionic substitution American Journal of Physiology – Heart and Circulatory Physiology High 12388308
1995 Kv beta 3 co-expressed with Kv1.4 accelerates both the fast and slow components of inactivation, increases the contribution of the slow component, slows recovery from inactivation (in full-length but not N-terminal deleted Kv1.4), and slows deactivation, without strongly affecting activation voltage dependence. Two-electrode voltage clamp in Xenopus oocytes, co-expression of alpha and beta subunits The American Journal of Physiology Medium 7631872
1997 Truncated Kv1.1 polypeptide (Kv1.1N206Tag) forms heteromultimeric complexes with native Kv1.4 (and Kv1.5) in GH3 cells, retaining these complexes in the endoplasmic reticulum and preventing their trafficking to the plasma membrane, thereby acting as a dominant-negative suppressor. Double immunoprecipitation, [35S]methionine pulse-chase, subcellular fractionation, immunofluorescence confocal microscopy The Journal of Biological Chemistry High 9334228
1998 Kvbeta1.2 N-terminus (beta-ball) directly blocks both Kv1.4 and N-terminal-deleted Kv1.4; Kvbeta1-C (C-terminus alone) and Kvbeta2 enhance N-type inactivation of Kv1.4 allosterically without direct ball domain involvement; alpha-beta interaction is restricted to the N-terminus of Kv1.4 and the C-terminus of Kvbeta. Two-electrode voltage clamp in Xenopus oocytes, yeast two-hybrid, deletion mutants The Journal of Physiology Medium 9763623
1997 Kvbeta1.1 and Kvbeta2.1 both accelerate the activation time constant of Kv1.4 without altering voltage dependence of activation or steady-state inactivation; Kvbeta2.1, which lacks an N-terminal inactivation domain, is nearly as effective as Kvbeta1.1 at speeding activation. Two-electrode voltage clamp in Xenopus oocytes, co-expression Pflügers Archiv Medium 9359902
2001 Kvbeta2 NADPH-binding and putative catalytic site mutations do not disrupt Kvbeta2–Kv1.4 physical interaction (confirmed by yeast two-hybrid) but abolish the expression-enhancing effect of Kvbeta2 on Kv1.4 surface protein and current amplitude without affecting the rate of inactivation increase, suggesting NADPH binding/oxidoreductase activity mediates Kv1.4 processing/trafficking separately from inactivation modulation. Yeast two-hybrid, Xenopus oocyte co-expression, Western blot, site-directed mutagenesis The Journal of Biological Chemistry Medium 11024060
1998 Kv1.4 immunoreactivity in hippocampus is concentrated presynaptically on axons and axonal necks near excitatory synaptic boutons (mossy fiber and perforant path terminals), as established by confocal immunofluorescence and ultrastructural immunoelectron microscopy. Confocal immunofluorescence microscopy, ultrastructural immunoelectron microscopy The Journal of Neuroscience Medium 9437018
1996 N-type inactivation of Kv1.4 is mediated by the proximal N-terminal ball domain; a single inactivating Kv1.4 subunit confers inactivation on heteromultimers with non-inactivating Kv1.5, and rate of inactivation is indistinguishable in channels with one versus two inactivating subunits. Two-electrode voltage clamp in Xenopus oocytes, Kv1.4-Kv1.5 tandem fusion constructs, N-terminal deletion mutants The Journal of Membrane Biology Medium 8661510
1996 Oxidation of N-terminal cysteine residues by cysteine-modifying reagents (DTBNP, chloramine-T) removes Kv1.4 inactivation and slows deactivation; these effects are reversed by the reducing agent DTT, indicating redox state controls Kv1.4 gating. Whole-cell patch clamp in HEK-293 cells, cysteine-specific oxidizing and reducing agents Pflügers Archiv Medium 8584439
2001 Riluzole irreversibly slows Kv1.4 inactivation by an oxidative, voltage-dependent mechanism involving a cysteine in the N-terminal inactivation domain; this effect is abolished by reducing agents (DTT, glutathione) in the pipette and does not occur when applied at depolarized holding potentials (where the N-terminal is in the inactivated position), indicating the accessible cysteine is protected in the inactivated state. Whole-cell patch clamp in bovine adrenal zona fasciculata cells, pharmacological manipulation with antioxidants and nucleotide analogs The Journal of Pharmacology and Experimental Therapeutics Medium 11561084
2003 Quinidine blocks Kv1.4 through open channel block and subsequently promotes C-type inactivation by a voltage-dependent allosteric conformational change; interventions that prevent C-type inactivation (elevated extracellular K+ or K532Y mutation) abolish the time-dependent quinidine effect, and the V561A S6 mutation reduces channel affinity for both quinidine and the N-terminal domain. Two-electrode voltage clamp in Xenopus oocytes, site-directed mutagenesis (K532Y, V561A), extracellular K+ manipulation, mathematical modeling The Journal of Physiology High 12527726 14608006
2006 DPP10 (a dipeptidyl peptidase-related ancillary subunit) co-expressed with Kv1.4 accelerates time to peak current and shifts the half-inactivation potential of steady-state activation and inactivation to more negative values, but slows recovery from inactivation, demonstrating DPP10 as a modulator of Kv1.4 inactivation. Xenopus oocyte co-expression electrophysiology, DPP10 truncation mutants American Journal of Physiology – Cell Physiology Medium 16738002
2006 EA1 mutations (E325D, V404I, V408A, I177N) in Kv1.1 reduce the rate and degree of N-type inactivation and accelerate recovery from fast inactivation in heteromeric Kv1.4-Kv1.1/Kvbeta1.x channels; Kvbeta1.1 and Kvbeta1.2 modulate Kv1.4-1.1 channels by increasing N-type inactivation rate, slowing recovery, and accelerating cumulative inactivation. Two-electrode voltage clamp in Xenopus oocytes, tandem-linked Kv1.4-Kv1.1 constructs, co-expression with Kvbeta subunits The European Journal of Neuroscience Medium 17156368
2006 EA1 mutation F184C in Kv1.1 increases Zn2+ sensitivity of heteromeric Kv1.4-Kv1.1/Kvbeta1.1 channels; Zn2+ occupies a high-affinity and a low-affinity site in this heteromeric complex, slowing activation, increasing time to peak current, decreasing N-type inactivation rate and amount, and slowing repriming. Two-electrode voltage clamp in Xenopus oocytes, Zn2+ dose-response analysis, EA1 point mutant American Journal of Physiology – Cell Physiology Medium 16956965
2005 Ser229 in the T1 domain of Kv1.4 is phosphorylated by PKA in cultured rat cortical neurons; neuronal transmission stimuli (glutamate, high K+, K+ channel blockers) stimulate this phosphorylation via NMDA receptor-mediated Ca2+ influx, while tetrodotoxin and Ca2+ depletion inhibit it; S229A mutation increases Kv1.4 current density. In vitro protein kinase assay, phospho-specific antibody Western blot, site-directed mutagenesis, pharmacological dissection Journal of Neurochemistry Medium 16000151
2003 Arachidonic acid and cis-polyunsaturated fatty acids directly inhibit Kv1.4 current and accelerate inactivation kinetics in bovine adrenal zona fasciculata cells; this inhibition is kinetically distinct from TREK-1 activation and does not require formation of AA metabolites (ETYA also inhibits Kv1.4). Whole-cell patch clamp on native cells, pharmacological manipulation with fatty acid analogs and pathway inhibitors The Journal of Membrane Biology Medium 14724761
2003 Endothelin-1 acting via ETA receptor decreases Kv1.4 transient outward current by ~85% in Xenopus oocytes; mutagenesis identified two phosphorylation sites (PKC and CaMKII) in the Kv1.4 sequence responsible for ET-1-mediated suppression. Xenopus oocyte co-expression electrophysiology, ETA receptor co-expression, site-directed mutagenesis of phosphorylation sites Biochemical and Biophysical Research Communications Medium 14521958
2011 Position-dependent attenuation of Kv1.4 N-type inactivation by the Kv1.6 NIP domain requires Kv1.4 and Kv1.6 to be adjacent subunits in the tetramer; when separated by one Kv1.2 subunit, fast inactivation is restored; mutation of critical glutamates within the NIP abolishes suppression of inactivation. Gene concatenation to form single-chain heterotetramers expressed in HEK293 cells, whole-cell electrophysiology, NIP mutagenesis The Biochemical Journal High 21352098
2014 Synaptotagmin I directly interacts with the N-terminus of Kv1.4 (independent of other synaptic proteins) and delays Kv1.4 N-type fast inactivation in a Ca2+-dependent manner, as shown by Co-IP and patch-clamp in HEK293T cells. Co-immunoprecipitation, whole-cell patch clamp in HEK293T cells, mutagenesis of Kv1.4 N-terminus Molecular Brain Medium 24423395
2010 Electrostatic interaction between the positively charged (residues 83–98) and negatively charged (residues 123–137) segments of the Kv1.4 N-terminus accelerates N-type inactivation; neutralization or deletion of the positive segment, or making both segments the same charge, slows inactivation without altering voltage dependence of activation. Whole-cell patch clamp, site-directed and deletion mutagenesis of N-terminal charged segments Biochimica et Biophysica Acta Medium 20674541
2007 Ginsenoside Rg3 inhibits Kv1.4 current by interacting with the extracellular Lys531 residue (part of the K+ activation and TEA binding site); K531Y mutation abolishes Rg3 inhibition and makes the channel sensitive to external TEA; elevated external K+ also reduces Rg3 inhibition, and Rg3 promotes C-type inactivation via this residue. Xenopus oocyte two-electrode voltage clamp, site-directed mutagenesis (K531Y and others), docking modeling Molecular Pharmacology Medium 17959711
2016 A missense variant p.Arg89Gln in KCNA4 causes severe loss-of-function of Kv1.4 channels (significantly reduced current amplitude); co-expression of WT and R89Q mRNA in Xenopus oocytes confirms dominant-negative-like reduction in current, and KCNA4 interacts with synaptotagmin I, DLG1, and DLG2. Two-electrode voltage clamp in Xenopus oocytes, whole-exome sequencing, RT-PCR, co-immunoprecipitation/interaction assays Journal of Medical Genetics Medium 27582084
2021 Nucleoporin 50 (Nup50) directly binds the Kcna4 promoter region via its FG-repeat domain and activates Kcna4 transcription and translation; Nup50 overexpression increases Ito,s currents in cardiomyocytes and knockdown reduces them. Luciferase reporter assay, chromatin immunoprecipitation, immunofluorescence, whole-cell patch clamp in cardiomyocytes Journal of Cell Science Medium 34409458
2017 PKC and AMPK activation reduce Kv1.4 cell-surface expression and current levels; PI3K, SGK1, Nedd4-1, and Nedd4-2 do not affect Kv1.4 surface localization, distinguishing Kv1.4 trafficking regulation from related Kv channels. Confocal microscopy in MDCK cells, two-electrode voltage clamp in Xenopus oocytes, pharmacological kinase activation Channels Medium 29168928
2023 miR-448 directly binds the 3'-UTR of KCNA4 mRNA and reduces KCNA4 expression and Ito current; inhibition of miR-448 restores KCNA4 levels, establishing a post-transcriptional regulatory mechanism for Kv1.4 downregulation in ischemia. RNA pull-down assay, miR-448 decoy and binding site mutation, qRT-PCR, electrophysiology Heart Rhythm Medium 36693615
2000 Kv1.4-encoded slow transient outward current (Ito,s) is eliminated in Kv1.4 knockout mice; upregulation of Kv1.4 in ventricular myocytes of Kv4.2W362F-expressing mice underlies the appearance of slow Ito in those cells; double knockout/transgenic mice (Kv4.2W362F×Kv1.4−/−) lack both Ito,f and Ito,s, develop early afterdepolarizations, AV block, and ventricular tachycardia. Targeted gene knockout, transgenic mouse models, in vivo telemetric ECG, patch clamp of isolated myocytes Circulation Research High 10884375
1998 Knockdown of Kv1.4 by antisense oligonucleotides in rat hippocampus eliminates both early- and late-phase LTP and reduces paired-pulse facilitation (a presynaptic effect) in CA1 pyramidal neurons without affecting spatial memory or dentate gyrus LTP. Intraventricular antisense oligonucleotide injection, RT-PCR, Western blot, hippocampal slice electrophysiology, behavioral maze testing PNAS Medium 9844011
2025 A de novo missense variant Kv1.4-V558L (located in the S6 hinge/selectivity filter) causes severe loss-of-function in a cell-based patch-clamp system without significantly affecting channel trafficking or plasma membrane localization, associated with early-onset developmental epileptic encephalopathy. Whole-exome sequencing trio, patch-clamp in cell-based system, trafficking/localization assay Human Molecular Genetics Medium 40472070
2023 Tyramine acting via TAAR1 receptor reduces Kv1.4-mediated IA in trigeminal ganglion neurons through a Gβγ-dependent PKCθ signaling cascade; siRNA knockdown of Kv1.4 abolishes TAAR1-induced IA decrease and pain hypersensitivity, while lentiviral Kv1.4 overexpression occludes TAAR1 blockade analgesia. Whole-cell patch clamp, siRNA knockdown, lentiviral overexpression, PKC isoform inhibition, Gβγ inhibition, mouse behavioral pain assays The Journal of Headache and Pain Medium 37158881

Source papers

Stage 0 corpus · 94 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron 258 9459448
2000 Functional consequences of elimination of i(to,f) and i(to,s): early afterdepolarizations, atrioventricular block, and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit. Circulation research 140 10884375
1997 Frequency-dependent inactivation of mammalian A-type K+ channel KV1.4 regulated by Ca2+/calmodulin-dependent protein kinase. The Journal of neuroscience : the official journal of the Society for Neuroscience 137 9133364
1998 Presynaptic localization of Kv1.4-containing A-type potassium channels near excitatory synapses in the hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 112 9437018
1995 C-type inactivation controls recovery in a fast inactivating cardiac K+ channel (Kv1.4) expressed in Xenopus oocytes. The Journal of physiology 102 8788936
2000 Internalization of the Kv1.4 potassium channel is suppressed by clustering interactions with PSD-95. The Journal of biological chemistry 95 10625685
2003 Glycosylation affects the protein stability and cell surface expression of Kv1.4 but Not Kv1.1 potassium channels. A pore region determinant dictates the effect of glycosylation on trafficking. The Journal of biological chemistry 94 14688283
1998 The transient outward current in mice lacking the potassium channel gene Kv1.4. The Journal of physiology 92 9547391
2003 Differential recruitment of Kv1.4 and Kv4.2 to lipid rafts by PSD-95. The Journal of biological chemistry 90 14559911
1999 Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K+ current in rat ventricle. The American journal of physiology 88 10330244
1993 Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy. The Journal of clinical investigation 77 7691883
1999 Requirement of N-terminal cysteines of PSD-95 for PSD-95 multimerization and ternary complex formation, but not for binding to potassium channel Kv1.4. The Journal of biological chemistry 72 9867876
1998 Memory and long-term potentiation (LTP) dissociated: normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense. Proceedings of the National Academy of Sciences of the United States of America 70 9844011
2005 Novel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis. Journal of neuroimmunology 66 16182377
2006 Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons. Neuroscience 65 16889902
2015 Interaction of Cr(VI) reduction and denitrification by strain Pseudomonas aeruginosa PCN-2 under aerobic conditions. Bioresource technology 57 25795449
2010 Molecular dissection of I(A) in cortical pyramidal neurons reveals three distinct components encoded by Kv4.2, Kv4.3, and Kv1.4 alpha-subunits. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 20371829
2001 A discrete amino terminal domain of Kv1.5 and Kv1.4 potassium channels interacts with the spectrin repeats of alpha-actinin-2. FEBS letters 54 11389904
2006 Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2. The European journal of neuroscience 50 17156368
2011 Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis. Journal of neurology 46 22167224
2001 Ligand binding of the second PDZ domain regulates clustering of PSD-95 with the Kv1.4 potassium channel. The Journal of biological chemistry 46 11723117
2000 Inhibition of the K+ channel kv1.4 by acidosis: protonation of an extracellular histidine slows the recovery from N-type inactivation. The Journal of physiology 44 10896716
1995 Time- and voltage-dependent modulation of a Kv1.4 channel by a beta-subunit (Kv beta 3) cloned from ferret ventricle. The American journal of physiology 41 7631872
2013 Hyperexcitability of bladder afferent neurons associated with reduction of Kv1.4 α-subunit in rats with spinal cord injury. The Journal of urology 40 23896350
2009 Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 alpha-subunit in rats with cystitis. American journal of physiology. Regulatory, integrative and comparative physiology 39 19279288
2001 Neuroprotective agent riluzole dramatically slows inactivation of Kv1.4 potassium channels by a voltage-dependent oxidative mechanism. The Journal of pharmacology and experimental therapeutics 39 11561084
1998 Regulation of Kv4.2 and Kv1.4 K+ channel expression by myocardial hypertrophic factors in cultured newborn rat ventricular cells. Journal of molecular and cellular cardiology 39 9710812
2003 Modulation of native TREK-1 and Kv1.4 K+ channels by polyunsaturated fatty acids and lysophospholipids. The Journal of membrane biology 38 14724761
1994 Genomic organization, nucleotide sequence, biophysical properties, and localization of the voltage-gated K+ channel gene KCNA4/Kv1.4 to mouse chromosome 2/human 11p14 and mapping of KCNC1/Kv3.1 to mouse 7/human 11p14.3-p15.2 and KCNA1/Kv1.1 to human 12p13. Genomics 37 8020965
1997 A cellular model for long QT syndrome. Trapping of heteromultimeric complexes consisting of truncated Kv1.1 potassium channel polypeptides and native Kv1.4 and Kv1.5 channels in the endoplasmic reticulum. The Journal of biological chemistry 36 9334228
2003 Kv1.4 channel block by quinidine: evidence for a drug-induced allosteric effect. The Journal of physiology 35 12527726
2003 Dihydropyridine Ca2+ channel antagonists and agonists block Kv4.2, Kv4.3 and Kv1.4 K+ channels expressed in HEK293 cells. British journal of pharmacology 33 12788813
1996 Cysteine-modifying reagents alter the gating of the rat cloned potassium channel Kv1.4. Pflugers Archiv : European journal of physiology 33 8584439
1995 Antiarrhythmic and bradycardic drugs inhibit currents of cloned K+ channels, KV1.2 and KV1.4. European journal of pharmacology 32 7589202
2006 DPP10 is an inactivation modulatory protein of Kv4.3 and Kv1.4. American journal of physiology. Cell physiology 31 16738002
2002 Regulation of N- and C-type inactivation of Kv1.4 by pHo and K+: evidence for transmembrane communication. American journal of physiology. Heart and circulatory physiology 31 12388308
1996 N-type inactivation in the mammalian Shaker K+ channel Kv1.4. The Journal of membrane biology 31 8661510
2003 Trafficking of Kv1.4 potassium channels: interdependence of a pore region determinant and a cytoplasmic C-terminal VXXSL determinant in regulating cell-surface trafficking. The Biochemical journal 30 12901718
1996 Characterization of the transcription unit of mouse Kv1.4, a voltage-gated potassium channel gene. The Journal of biological chemistry 30 8663090
2016 Potential application of aerobic denitrifying bacterium Pseudomonas aeruginosa PCN-2 in nitrogen oxides (NOx) removal from flue gas. Journal of hazardous materials 29 27469045
2006 Curcumin potently blocks Kv1.4 potassium channels. Biochemical and biophysical research communications 29 16647042
2003 Immunohistochemical localization of the voltage-gated potassium channel subunit Kv1.4 in the central nervous system of the adult rat. Journal of chemical neuroanatomy 29 14615029
1998 Functional expression of GFP-tagged Kv1.3 and Kv1.4 channels in HEK 293 cells. The European journal of neuroscience 29 9875368
2009 Arachidonic acid potently inhibits both postsynaptic-type Kv4.2 and presynaptic-type Kv1.4 IA potassium channels. The European journal of neuroscience 28 19453640
2001 Mutations in the Kv beta 2 binding site for NADPH and their effects on Kv1.4. The Journal of biological chemistry 28 11024060
2006 Pituitary adenylate cyclase activating polypeptide reduces expression of Kv1.4 and Kv4.2 subunits underlying A-type K(+) current in adult mouse olfactory neuroepithelia. Neuroscience 27 16426762
2014 Reduced excitability of gp130-deficient nociceptors is associated with increased voltage-gated potassium currents and Kcna4 channel upregulation. Pflugers Archiv : European journal of physiology 26 24463703
2006 Episodic ataxia type 1 mutation F184C alters Zn2+-induced modulation of the human K+ channel Kv1.4-Kv1.1/Kvbeta1.1. American journal of physiology. Cell physiology 25 16956965
2003 Inactivation and recovery in Kv1.4 K+ channels: lipophilic interactions at the intracellular mouth of the pore. The Journal of physiology 25 14608006
1999 Co-localization of Shaker A-type K+ channel (Kv1.4) and AMPA-glutamate receptor (GluR4) immunoreactivities to dendrites of OFF-bipolar cells of goldfish retina. Journal of neurocytology 23 10573608
2005 Immunohistochemical co-expression of carbonic anhydrase II with Kv1.4 and TRPV1 in rat small-diameter trigeminal ganglion neurons. Brain research 22 15885224
2003 Fluoxetine blocks cloned neuronal A-type K+ channels Kv1.4. Neuroreport 22 14663209
1998 Separable effects of human Kvbeta1.2 N- and C-termini on inactivation and expression of human Kv1.4. The Journal of physiology 22 9763623
1997 Modification of rat brain Kv1.4 channel gating by association with accessory Kvbeta1.1 and beta2.1 subunits. Pflugers Archiv : European journal of physiology 22 9359902
2015 IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Circadian Period of PER2 Expression in the Suprachiasmatic Nucleus. Journal of biological rhythms 21 26152125
2003 Differential inhibition of transient outward currents of Kv1.4 and Kv4.3 by endothelin. Biochemical and biophysical research communications 21 14521958
2000 A bovine adrenocortical Kv1.4 K(+) channel whose expression is potently inhibited by ACTH. The Journal of biological chemistry 21 10913143
2016 KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability. Journal of medical genetics 20 27582084
2007 Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue. Molecular pharmacology 20 17959711
2004 K+ activation of kir3.1/kir3.4 and kv1.4 K+ channels is regulated by extracellular charges. Biophysical journal 19 15454439
2005 Neuronal transmission stimulates the phosphorylation of Kv1.4 channel at Ser229 through protein kinase A1. Journal of neurochemistry 16 16000151
2000 Subcellular compartmentalization of a potassium channel (Kv1.4): preferential distribution in dendrites and dendritic spines of neurons in the dorsal cochlear nucleus. The European journal of neuroscience 16 11122345
2022 Nivolumab-induced Myositis and Myocarditis with Positive Anti-titin Antibody and Anti-voltage-gated Potassium Channel Kv1.4 Antibody. Internal medicine (Tokyo, Japan) 15 35314545
2007 Re-expression of a developmentally restricted potassium channel in autoimmune demyelination: Kv1.4 is implicated in oligodendroglial proliferation. The American journal of pathology 15 17600124
2019 Interleukin 6 decreases nociceptor expression of the potassium channel KV1.4 in a rat model of hand-arm vibration syndrome. Pain 14 31335655
2011 A model of the interaction between N-type and C-type inactivation in Kv1.4 channels. Biophysical journal 13 21190652
2004 The Kv4.2 N-terminal restores fast inactivation and confers KChlP2 modulatory effects on N-terminal-deleted Kv1.4 channels. Pflugers Archiv : European journal of physiology 13 15452711
2017 Regulation of Kv1.4 potassium channels by PKC and AMPK kinases. Channels (Austin, Tex.) 12 29168928
2007 Kv1.4 subunit expression is decreased in neurons of painful human pulp. Journal of endodontics 12 17804321
2002 Modulation of voltage-gated K(+) channels Kv11 and Kv1 4 by forskolin. Neuropharmacology 12 12243774
1999 Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel. Brain research 12 10411982
2002 Determinants of 4-aminopyridine sensitivity in a human brain kv1.4 k(+) channel: phenylalanine substitutions in leucine heptad repeat region stabilize channel closed state. Molecular pharmacology 11 11901231
2020 Open channel block of Kv1.4 potassium channels by aripiprazole. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 10 33093275
2011 Position-dependent attenuation by Kv1.6 of N-type inactivation of Kv1.4-containing channels. The Biochemical journal 10 21352098
2023 miR-448 regulates potassium voltage-gated channel subfamily A member 4 (KCNA4) in ischemia and heart failure. Heart rhythm 9 36693615
2009 The effects of ginsenoside Rg(3) on human Kv1.4 channel currents without the N-terminal rapid inactivation domain. Biological & pharmaceutical bulletin 9 19336893
2022 Insight into sulfamethoxazole effects on aerobic denitrification by strain Pseudomonas aeruginosa PCN-2: From simultaneous degradation performance to transcriptome analysis. Chemosphere 8 36493888
2023 Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors. The journal of headache and pain 7 37158881
2021 Nucleoporin 50 mediates Kcna4 transcription to regulate cardiac electrical activity. Journal of cell science 6 34409458
2014 Synaptotagmin I delays the fast inactivation of Kv1.4 channel through interaction with its N-terminus. Molecular brain 6 24423395
2023 Anti-Kv1.4 Antibody Without Myasthenia Gravis: A Rare Cause of Autoimmune Myocarditis and Myositis. JACC. Case reports 4 36909266
2021 Marked Respiratory Failure in an Ambulant Patient with Immune-mediated Necrotizing Myopathy and Anti-Kv1.4 and Anti-titin Antibodies. Internal medicine (Tokyo, Japan) 4 33642484
2020 [A case of sporadic late-onset nemaline myopathy associated with myasthenia gravis positive for anti-titin antibody and anti-Kv1.4 antibody]. Rinsho shinkeigaku = Clinical neurology 4 32536668
2018 Molecular basis involved in the blocking effect of antidepressant metergoline on C-type inactivation of Kv1.4 channel. Neuropharmacology 4 30465811
2010 Electrostatic interaction in the NH(2)-terminus accelerates inactivation of the Kv1.4 channel. Biochimica et biophysica acta 3 20674541
2009 NMR assignments of a 48 kDa tetramer of the T1 domain of the mammalian voltage gated potassium channel Kv1.4. Biomolecular NMR assignments 2 19888682
2025 De novo missense variants of KCNA3, KCNA4, and KCNA6 cause early onset developmental epileptic encephalopathy. Human molecular genetics 1 40472070
2023 Amyloid-β Protein Precursor Regulates Electrophysiological Properties in the Hippocampus via Altered Kv1.4 Expression and Function in Mice. Journal of Alzheimer's disease : JAD 1 36872774
2023 Anti-Kv1.4 Antibody-positive Nivolumab-induced Myasthenia Gravis and Myositis Presenting with Bilateral Ptosis and Demonstrating Different Pathophysiologies. Internal medicine (Tokyo, Japan) 1 37839874
1998 Influence of outer pore residue K533 on the inhibition of Kv1.4 potassium channels by n-alkyl sulphate anions. Pflugers Archiv : European journal of physiology 1 9683737
1991 A polymorphic region defined by pCN2 (the 3' nontranslated region of N-ras) maps to chromosome 9cen-p12. Human genetics 1 1879830
2026 Accessibility at a primed distal Fshb-Kcna4 super-enhancer is facilitated by Foxl2 during gonadotrope differentiation. Endocrinology 0 41823422
2023 [A case of anti-acetylcholine receptor antibody-positive ocular myasthenia gravis with anti-titin antibody and anti-Kv1.4 antibody positive inflammatory myopathy]. Rinsho shinkeigaku = Clinical neurology 0 37989286
2019 KCNA4 Gene Variant is Auxiliary in Endurance Running Performance Level. International journal of sports medicine 0 30812034

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