Affinage

KCNA3

Potassium voltage-gated channel subfamily A member 3 · UniProt P22001

Length
575 aa
Mass
63.8 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNA3 (Kv1.3) is a voltage-gated potassium channel that functions as a central regulator of membrane potential in immune cells, neurons, and metabolically active tissues, coupling electrical signaling to cellular activation, proliferation, and apoptosis. The channel assembles as a homotetramer via its N-terminal T1 domain and is gated by voltage-dependent conformational changes; its current is suppressed by src-family and EGF receptor tyrosine kinase phosphorylation at Y449/Y479, upregulated by PKA, and dominantly inhibited by PKC (PMID:8774427, PMID:9348331, PMID:9277360). In effector memory T cells and microglia, Kv1.3 redistributes to the immunological synapse during antigen presentation, where it sustains the electrochemical driving force for Ca²⁺ influx through CRAC channels to control cytokine production and proliferation; in microglia, Kv1.3 is required for NADPH oxidase-dependent respiratory burst and pro-inflammatory activation, and its blockade attenuates neuroinflammation and amyloid pathology (PMID:17088564, PMID:16079396, PMID:30043400, PMID:33649184). Beyond immune regulation, Kv1.3 resides in the inner mitochondrial membrane where Bax binding triggers cytochrome c release and apoptosis, promotes vascular smooth muscle cell proliferation through an ion flux-independent MEK-ERK pathway requiring C-terminal Y447 phosphorylation, and regulates whole-body energy homeostasis as demonstrated by obesity resistance in Kv1.3-deficient mice (PMID:18818304, PMID:22383699, PMID:26655221, PMID:12588802).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Establishing the molecular basis of kinase regulation: tyrosine phosphorylation at Y449 by src and EGFR was identified as the critical post-translational modification suppressing Kv1.3 current, answering how growth factor signaling directly modulates channel activity.

    Evidence Co-expression with v-src/EGFR in HEK293 cells, immunoprecipitation, patch-clamp, Y449F mutagenesis

    PMID:8774427

    Open questions at the time
    • Structural basis for how Y449 phosphorylation alters gating not resolved
    • Whether phosphorylation affects channel trafficking vs. gating kinetics not distinguished
  2. 1997 High

    Demonstrating that Kv1.3 forms functional homotetramers and that distinct receptor tyrosine kinases modulate the channel through separable mechanisms (Y479 for EGFR vs. a distinct site for insulin receptor), establishing the quaternary structure and multi-input phosphoregulatory logic of the channel.

    Evidence Purification/EM/reconstitution of tetramers; mutagenesis distinguishing EGFR (Y479F) and insulin receptor effects in HEK293 cells; PKA/PKC pharmacology in primary human T cells

    PMID:8868051 PMID:8999950 PMID:9277360 PMID:9348331

    Open questions at the time
    • Insulin receptor phosphorylation site on Kv1.3 not identified
    • Stoichiometry of kinase-channel interaction in native cells unknown
  3. 2000 High

    Defining Kv1.3 biogenesis: S2 acts as the initial signal sequence for ER membrane integration, and the T1 domain prevents S1 from initiating translocation, resolving how a six-transmembrane channel achieves correct topology during co-translational folding.

    Evidence Protease protection, glycosylation, and carbonate extraction assays on ER biogenesis intermediates

    PMID:10651649

    Open questions at the time
    • Role of ER chaperones in Kv1.3 folding not addressed
    • Whether heteromeric assembly alters biogenesis pathway unknown
  4. 2003 High

    Kv1.3 knockout mice revealed that the channel is dispensable for lymphocyte development (compensated by chloride current upregulation) but essential for body weight regulation, establishing an unexpected metabolic role and demonstrating functional redundancy in immune cells.

    Evidence Gene-targeted KO mice with electrophysiology, flow cytometry, indirect calorimetry, high-fat diet challenge

    PMID:12588802 PMID:12878608

    Open questions at the time
    • Mechanism linking Kv1.3 to basal metabolic rate not identified at molecular level
    • Identity of compensatory chloride channel unknown
  5. 2004 High

    Discovery that Kv1.3 redistributes to the immunological synapse in cytotoxic T lymphocytes established the channel as a spatially regulated component of immune activation rather than a uniformly distributed membrane conductance.

    Evidence Confocal microscopy of FLAG-tagged Kv1.3 in CTL–target cell conjugates

    PMID:14745040

    Open questions at the time
    • Molecular signals driving IS recruitment not identified
    • Whether IS localization is required for killing function not tested
  6. 2005 High

    Microglial Kv1.3 was shown to be required for NADPH oxidase-mediated respiratory burst and peroxynitrite-dependent neurotoxicity, placing Kv1.3 as a cell-autonomous driver of neuroinflammatory damage distinct from neuronal channel activity.

    Evidence Transwell co-culture separating microglia from neurons, Kv1.3 blockers, respiratory burst and neurotoxicity assays

    PMID:16079396

    Open questions at the time
    • How Kv1.3 activity couples to NADPH oxidase assembly not resolved
    • Whether Kv1.3 regulation of microglial toxicity operates through membrane potential alone or involves non-conducting signaling
  7. 2006 High

    Functional integration of Kv1.3 at the IS was demonstrated: the channel colocalizes with signaling scaffolds (SAP97, p56lck) and its blockade impairs Ca²⁺ signaling and cytokine production at the synapse, establishing Kv1.3 as the dominant membrane potential regulator controlling effector memory T cell activation.

    Evidence Confocal co-localization, Ca²⁺ and cytokine assays with selective Kv1.3 blockers in effector memory T cells

    PMID:17088564

    Open questions at the time
    • Mechanism of selective IS recruitment vs. IKCa1 exclusion not defined
    • Relative contributions of Kv1.3 and KCa3.1 at different T cell differentiation stages not fully resolved
  8. 2008 High

    Identification of Kv1.3 in the inner mitochondrial membrane and demonstration that Bax directly inhibits it to trigger apoptosis via hyperpolarization, ROS, and cytochrome c release established a non-canonical mitochondrial function for a plasma membrane ion channel.

    Evidence Kv1.3 KO/siRNA, mitochondria-targeted retransfection, recombinant Bax incubation with isolated mitochondria, Bax K128A mutagenesis

    PMID:18818304

    Open questions at the time
    • How Kv1.3 is routed to mitochondria vs. plasma membrane not resolved at this point
    • Whether mitochondrial Kv1.3 forms homotetramers or heteromeric assemblies in IMM unknown
  9. 2012 High

    A non-conducting signaling function was established: Kv1.3 promotes vascular smooth muscle cell proliferation through voltage-dependent conformational changes independent of K⁺ flux, and diet-induced obesity resistance in KO mice depends on olfactory bulb circuits.

    Evidence Poreless and gating mutants in proliferation assays; bilateral olfactory bulbectomy in KO mice with metabolic phenotyping

    PMID:22383699 PMID:22435906

    Open questions at the time
    • Identity of the proliferative signaling partner sensing conformational change not known
    • Molecular mechanism linking olfactory Kv1.3 to systemic energy expenditure unresolved
  10. 2015 High

    The non-conducting proliferative mechanism was resolved to the C-terminus: MEK-ERK1/2-dependent phosphorylation of Y447 upon channel opening mediates proliferative signaling, and EGF-triggered ERK1/2-dependent threonine phosphorylation drives clathrin-mediated endocytosis and lysosomal degradation of the channel.

    Evidence Y447A/S459A mutants, chimeric channels, MEK/ERK inhibitors, clathrin inhibitors, trafficking assays

    PMID:26542799 PMID:26655221

    Open questions at the time
    • Whether ERK-mediated endocytosis serves as negative feedback on the proliferative signal not tested
    • Specific threonine residue(s) mediating endocytosis not mapped
  11. 2016 Medium

    Two mechanisms controlling Kv1.3 surface density were defined: KCNE4 retains Kv1.3 in the ER by masking its YMVIEE surface-targeting motif, while caveolin 1 localizes the channel to lipid raft microdomains via an N-terminal caveolin-binding domain.

    Evidence Co-IP, deletion mutants, lipid raft fractionation, immunofluorescence

    PMID:26931497 PMID:27802162

    Open questions at the time
    • Stoichiometry of KCNE4:Kv1.3 complexes not determined
    • Whether caveolar vs. non-caveolar Kv1.3 pools have distinct electrophysiological properties in native cells untested
  12. 2020 High

    In microglia, Kv1.3 was mechanistically linked to purinergic signaling: it counteracts P2X4-mediated depolarization to maintain the driving force for Ca²⁺ entry, and Fyn kinase directly binds Kv1.3 to upregulate its expression and post-translational modification in response to aggregated α-synuclein, connecting the channel to Parkinson's disease neuroinflammation.

    Evidence Electrophysiological dissection of Kv1.3–P2X4 interplay; proximity ligation assay for Fyn–Kv1.3 binding; KO and PAP-1 blockade in PD models

    PMID:32525239 PMID:32597830

    Open questions at the time
    • Whether Fyn phosphorylation of Kv1.3 occurs at the same Y449 site as src not determined
    • Direct structural basis for P2X4–Kv1.3 functional coupling unknown
  13. 2022 High

    Cryo-EM structures of human Kv1.3 revealed the pore architecture and defined two distinct inhibition mechanisms — a nanobody that allosterically collapses the pore via voltage-sensor binding, and a toxin that plugs the pore with a lysine residue — providing a structural framework for therapeutic targeting.

    Evidence Cryo-EM at near-atomic resolution with nanobody and antibody-toxin fusion complexes, functional validation

    PMID:35788586

    Open questions at the time
    • No structure of Kv1.3 with regulatory subunits (KCNE4, Kvβ2, caveolin) available
    • Structural basis for non-conducting conformational signaling not captured
  14. 2022 Medium

    The mitochondrial import pathway of Kv1.3 was defined: it uses the TIM23 complex without a classical presequence, with cooperative transmembrane domain targeting assisted by cytosolic HSP70/HSP90 chaperones, and Kv1.3 was shown to regulate neutrophil store-operated Ca²⁺ entry and extravasation.

    Evidence TIM23 assays, HSP inhibition, domain mapping; Kv1.3 KO mice with intravital microscopy and Ca²⁺ imaging in neutrophils

    PMID:33881519 PMID:35402277

    Open questions at the time
    • Signals that partition Kv1.3 between plasma membrane, mitochondrial, and nuclear pools not identified
    • Whether mitochondrial import occurs co- or post-translationally unclear
  15. 2024 Medium

    Proximity proteomics mapped domain-specific interactomes: the N-terminus mediates surface and mitochondrial trafficking (NUDC, TIMM50), while the C-terminal PDZ-binding domain couples to immune signaling proteins (STAT1, TLR2, C3), with Kv1.3 blockade reducing interferon-dependent STAT1 activation in microglia.

    Evidence TurboID proximity labeling in BV-2 microglia, PDZ-domain deletion mutant, Western blot for STAT1 phosphorylation

    PMID:38936775

    Open questions at the time
    • Proximity labeling interactions await reciprocal validation
    • Whether STAT1 coupling is direct or scaffold-mediated not resolved
    • Functional significance of C3 interaction not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis of non-conducting conformational signaling through Y447, the decision mechanism partitioning Kv1.3 among plasma membrane, mitochondrial, and nuclear pools, and the molecular pathway linking olfactory bulb Kv1.3 to systemic energy expenditure.
  • No structure of Kv1.3 in a signaling-competent non-conducting state
  • No molecular mechanism for metabolic regulation via olfactory Kv1.3
  • Role of heteromeric Kv1 assembly in vivo poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 7 GO:0005739 mitochondrion 2 GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 7 R-HSA-382551 Transport of small molecules 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
BAXCAV1DLG1FYNGRB10KCNE2KCNE4STAT1
Complex memberships
Kv1.3 homotetramerKv1.3–KCNE2–KCNQ1 complexKv1.3–KCNE4 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 Cryo-EM structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker were determined. The nanobody binds voltage-sensing domains and the pore domain to induce an inactive pore conformation (without directly blocking the pore), whereas the antibody-toxin fusion docks its toxin domain at the extracellular mouth, inserting a critical lysine into the pore to stabilize an active conformation while blocking ion permeation. Cryo-EM structure determination with functional validation Nature Communications High 35788586
1996 Tyrosine phosphorylation of Kv1.3 at residue Y449 by endogenous and exogenous tyrosine kinases (v-src, EGF receptor) suppresses channel current; mutation Y449F abolishes both the pervanadate-induced phosphorylation and the associated current decrease, establishing Y449 as the critical regulatory site. Co-expression with constitutively active v-src and EGF receptor in HEK293 cells, immunoprecipitation/Western blot with anti-phosphotyrosine antibody, patch-clamp electrophysiology, site-directed mutagenesis Journal of Neuroscience High 8774427
1997 EGF receptor and insulin receptor tyrosine kinases modulate Kv1.3 current by distinct mechanisms: EGF treatment suppresses peak current and accelerates C-type inactivation via tyrosine phosphorylation at Y479 (mutation Y479F blocks the effect), while insulin suppresses peak current without altering inactivation kinetics. Co-expression in HEK293 cells, patch-clamp electrophysiology, tyrosine kinase inhibitor treatment, site-directed mutagenesis, receptor-blocking antibody Journal of General Physiology High 9348331
2000 Src-family tyrosine kinases phosphorylate Kv1.3 and suppress its current in microglia; oxygen/glucose deprivation increases Kv1.3 tyrosine phosphorylation via reactive oxygen species and src activation, downregulating channel activity. Kv1.3 and src co-precipitate with the scaffolding protein PSD-95 in microglia. Co-transfection of v-src with Kv1.3 in microglia-like MLS-9 cells, patch-clamp electrophysiology, biochemical tyrosine phosphorylation assay, co-immunoprecipitation, src peptide activator/PTK inhibitors European Journal of Neuroscience High 10886336
2000 Biogenesis of Kv1.3 in the endoplasmic reticulum was characterized: S1 and S2 are the primary transmembrane anchors, S4 independently integrates into the membrane, and S2 likely functions as the initial signal sequence for topology establishment. The N-terminal T1 domain prevents S1 from initiating translocation, and multiple transmembrane segments cooperate during topogenesis. Protease protection, glycosylation, and carbonate extraction assays on ER biogenesis intermediates Biochemistry High 10651649
2004 The T1 tetramerization domain of Kv1.3 acquires compact (likely helical) secondary structure within the ribosomal tunnel and tertiary structure only after emerging from the ribosomal exit tunnel following complete synthesis of the T1-S1 linker. Biogenic intermediate analysis, folding and accessibility assays on nascent peptides within and outside the ribosome Neuron High 15473968
1997 Purified Kv1.3 forms homotetramers (~270 kDa by sucrose gradient sedimentation) with dimensions of ~65×65 Å by electron microscopy; the channel reconstituted in lipid bilayers produces voltage-dependent, K+-selective currents blocked by margatoxin and stichodactylatoxin. Kv1.3 carries a ~2 kDa N-glycosylation in the S1-S2 loop that does not alter biophysical properties. Nickel-chelate purification, sucrose gradient sedimentation, negative-stain EM, lipid bilayer reconstitution, electrophysiology, site-directed mutagenesis of glycosylation site Journal of Biological Chemistry High 8999950
1996 Kv1.3 subunits assemble randomly into tetramers in T lymphocytes (Jurkat cells); membrane-inserted tetramers do not dissociate and reassemble. A truncated Kv1.3 containing the N-terminus and first two transmembrane segments suppresses endogenous Kv1.3 current by forming non-functional heterotetramers. Kinetic analysis of C-type inactivation of heterotetrameric channels, heterologous expression of mutant and truncated subunits in Jurkat cells, patch-clamp electrophysiology Journal of General Physiology High 8868051
2008 Kv1.3 is located in the inner mitochondrial membrane of lymphocytes. Bax binds to and inhibits mitochondrial Kv1.3, triggering mitochondrial hyperpolarization, ROS production, and cytochrome c release. Cells lacking Kv1.3 or expressing mitochondria-targeted Kv1.3 mutants resist Bax-induced apoptosis; K128 of Bax (homologous to the channel-contacting residue in Kv1.3-blocking toxins) is required for this interaction. Kv1.3 knockout and siRNA knockdown, mitochondria-targeted Kv1.3 retransfection, co-incubation of isolated mitochondria with recombinant Bax/t-Bid, measurement of membrane potential, ROS, and cytochrome c release, Bax K128A mutagenesis PNAS High 18818304
2006 During antigen presentation in effector memory T cells, Kv1.3 traffics to the immunological synapse (IS) where it colocalizes with Kvβ2, SAP97, ZIP, p56(lck), and CD4; Kv1.3 inhibitors suppress Ca2+-signaling and cytokine production at the IS without preventing synapse formation. Confocal microscopy of FLAG-tagged Kv1.3, co-localization with IS markers, Ca2+ signaling assays, cytokine production assays with selective Kv1.3 blockers PNAS High 17088564
2004 Kv1.3 channels bearing a FLAG epitope accumulate at the immunological synapse (IS) formed between cytotoxic T lymphocytes and specific target cells, shifting from a patchy distribution in non-engaged CTLs. Confocal laser-scanning microscopy of FLAG-tagged Kv1.3 in CTLs interacting with target lymphocytes PNAS High 14745040
2009 Kv1.3 channel activity in the IS is functionally modified: activation kinetics slow, inactivation rate increases, and voltage-dependence of steady-state activation shifts to more depolarized potentials. The increased inactivation rate is attributable to dephosphorylation of the channel within the IS. Whole-cell patch-clamp of T cells in IS vs. standalone, protein kinase inhibitors (PKC, PKA, p56Lck) Immunology Letters Medium 19477198
2009 In SLE T cells, Kv1.3 prematurely exits the immunological synapse, correlating with sustained Ca2+ influx; in normal T cells, Kv1.3 remains in the IS and Ca2+ influx terminates normally, suggesting Kv1.3 IS retention controls Ca2+ signal duration. Two-photon microscopy correlating cytosolic Ca2+ concentrations and Kv1.3 trafficking during IS formation in SLE vs. normal T cells Cell Calcium Medium 19959227
2005 The T1 tetramerization domain of Kv1.3 is necessary and sufficient for axonal targeting in cortical pyramidal neurons; it directs transport vesicle trafficking to axons, not through compartment-specific endocytosis or vesicle docking. Expression of T1-fusion proteins in cortical neuron slices, live imaging of GFP-labeled transport vesicles, confocal microscopy European Journal of Neuroscience Medium 16262625
2010 Kv1.3 is localized in presynaptic terminals (calyx of Held) in the medial nucleus of the trapezoid body, with a tonotopic gradient (highest in lateral/low-frequency region), confirmed by co-immunolocalization with synaptic markers and immunogold EM; no staining in Kv1.3−/− mice. Confocal immunofluorescence, co-localization with synaptophysin/syntaxin/synaptotagmin, immunogold electron microscopy, Kv1.3 KO controls Journal of Comparative Neurology High 20575068
2003 Kv1.3-deficient mice have no voltage-dependent K+ current in thymocytes but show ~50-fold upregulation of chloride current as a compensatory mechanism; no defects in lymphocyte numbers, thymocyte apoptosis, or T cell proliferation in mice. Gene targeting/KO, whole-cell patch-clamp electrophysiology, flow cytometry of lymphocyte populations, RT-PCR and Western blot for channel subunits Journal of Biological Chemistry High 12878608
2003 Kv1.3-deficient mice weigh significantly less than controls, are protected from diet-induced obesity, and have significantly higher basal metabolic rate without altered food intake, demonstrating that Kv1.3 channels participate in energy homeostasis and body weight regulation. Gene-targeted KO mice, indirect calorimetry, high-fat diet challenge, body weight and fat pad measurements Human Molecular Genetics High 12588802
2012 Diet-induced obesity resistance in Kv1.3−/− mice is olfactory bulb-dependent: bilateral olfactory bulbectomy abolishes resistance to high-fat diet-induced obesity and the associated upregulation of light-phase energy expenditure in Kv1.3−/− mice. Bilateral olfactory bulbectomy in Kv1.3+/+ and Kv1.3−/− mice, indirect calorimetry, body weight and adiposity measurement on high-fat diet Journal of Neuroendocrinology Medium 22435906
2003 Fas receptor activation stimulates Kv1.3 channel activity in Jurkat T cells in a caspase 8- and FADD-dependent (but caspase 3-independent) manner, producing a sustained outward K+ current that contributes to apoptotic K+ efflux; PKC activation prevents both Kv1.3 stimulation and apoptosis. Whole-cell patch-clamp in Jurkat cells, Fas ligand treatment, selective Kv1.3 toxin blockers, caspase inhibitors, PKC stimulation Journal of Biological Chemistry High 12807917
1997 Native Kv1.3 current in human T lymphocytes is upregulated by cAMP-dependent protein kinase A (PKA) activation and by phosphatase inhibition, but PKC-dependent phosphorylation acts as a dominant suppressive switch that overrides PKA-induced upregulation. Whole-cell patch-clamp of primary human T cells with PKA activators/inhibitors, PKC activators, phosphatase inhibitor okadaic acid American Journal of Physiology Medium 9277360
2009 The adaptor protein nShc forms a direct protein-protein interaction with Kv1.3 (independent of BDNF-induced phosphorylation), while Grb10 decreases total Kv1.3 expression at the membrane surface via its SH2 domains binding to basally phosphorylated tyrosines Y111-113 and Y449, and both adaptors prevent BDNF/TrkB-induced current suppression of Kv1.3. Co-immunoprecipitation, Western blot, site-directed mutagenesis of tyrosine residues, patch-clamp electrophysiology, immunocytochemistry in olfactory bulb and HEK293 cells BMC Neuroscience Medium 19166614
2010 Fyn kinase modulates transcriptional upregulation and posttranslational modification of microglial Kv1.3 in response to aggregated α-synuclein; Fyn directly binds to Kv1.3 as demonstrated by Duolink proximity ligation assay, and Kv1.3 KO or PAP-1 blockade reduces neuroinflammatory response and neurodegeneration in PD models. Proximity ligation assay, patch-clamp electrophysiology, Kv1.3 KO primary microglia, PAP-1 pharmacological blockade in multiple animal models of PD Journal of Clinical Investigation High 32597830
2012 Kv1.3 channels promote cell proliferation in vascular smooth muscle cells (VSMCs) via an ion-flux-independent mechanism that requires the voltage-dependent conformational change of the channel; 'poreless' (non-conducting) Kv1.3 mutants retain pro-proliferative effect, but mutants lacking voltage-dependence of gating do not. Heterologous expression of Kv1.3, Kv1.5, poreless mutants, and voltage-gating mutants in HEK cells; proliferation assays; electrophysiology; selective channel blockers in VSMCs Arteriosclerosis, Thrombosis, and Vascular Biology High 22383699
2015 Kv1.3-induced proliferation requires the C-terminal domain, specifically residues Y447 and S459; voltage-dependent conformational changes from closed to open state induce MEK-ERK1/2-dependent phosphorylation of Y447, providing a signaling mechanism for K+ flux-independent proliferative signaling. Chimeric Kv1.3-Kv1.5 channels, point mutations (Y447A, S459A), GFP/cherry fusion constructs, immunocytochemistry, electrophysiology, proliferation assays, MEK/ERK inhibitors Journal of Biological Chemistry High 26655221
2011 KCNE2 forms heteromeric complexes with KCNA3 (Kv1.3) and KCNQ1 in the choroid plexus epithelium apical membrane; Kcne2 deletion increases outward K+ current (inhibited by margatoxin for KCNA3 component), alters polarity of KCNA3/KCNQ1 trafficking, hyperpolarizes the CPe membrane, and increases CSF [Cl−]. Kcne2 KO mouse tissue as negative control, whole-cell patch-clamp of choroid plexus epithelium, selective K+ channel inhibitors, immunohistochemistry, CSF ion measurement FASEB Journal High 21859894
2016 KCNE4 physically interacts with Kv1.3 via the C-terminal domain of Kv1.3 (necessary and sufficient for interaction), retaining the channel intracellularly via two additive mechanisms: masking the YMVIEE surface-targeting motif at the C-terminus and an ER retention motif in KCNE4. Co-immunoprecipitation, deletion/truncation mutants, immunofluorescence of intracellular localization, electrophysiology Journal of Cell Science Medium 27802162
2016 Kv1.3 localizes to caveolar lipid raft microdomains via interaction of its N-terminal caveolin-binding domain (FQRQVWLLF motif) with caveolin 1; variations in this motif or ancillary associations impair caveolin recognition and alter surface localization. Caveolin-binding domain mutagenesis, co-immunoprecipitation with caveolin 1, lipid raft fractionation, immunofluorescence Scientific Reports Medium 26931497
2018 Kv1.3 localization in caveolae via caveolin 1 is required for proper insulin-dependent phosphorylation of the channel and glucose uptake in mature adipocytes; using caveolin 1-deficient cells, Kv1.3 outside caveolar microdomains shows impaired insulin-induced phosphorylation. Caveolin 1-deficient 3T3-L1 adipocyte cell line, glucose uptake assay, Kv1.3 phosphorylation assay, immunofluorescence Cellular and Molecular Life Sciences Medium 29947924
2022 Kv1.3 translocates to the inner mitochondrial membrane via the TIM23 complex in an unconventional manner (multimembrane spanning protein without a classical N-terminal presequence); transmembrane domains cooperatively mediate mitochondrial targeting and cytosolic HSP70/HSP90 chaperone complex is required for this routing. TIM23 complex functional assays, mitochondrial import assays, HSP70/HSP90 inhibition, domain mapping by truncation/chimera analysis Frontiers in Oncology Medium 35402277
2015 Kv1.3 channels are expressed in the nuclei of multiple cancer cell lines and human brain tissues; nuclear Kv1.3 is functional (margatoxin hyperpolarizes nuclear membrane), forms a complex with upstream binding factor 1, and blockade induces phosphorylation of CREB and c-Fos; Sp1 transcription factor directly binds the Kv1.3 gene promoter. Subcellular fractionation/Western blot, nuclear membrane patch-clamp, Kv1.3 siRNA knockdown, co-immunoprecipitation, chromatin immunoprecipitation Journal of Biological Chemistry Medium 25829491
2015 EGF receptor activation triggers ERK1/2-mediated threonine phosphorylation of Kv1.3, leading to clathrin-dependent endocytosis and lysosomal degradation of the channel; PDZ and SH3 domain-interacting motifs and known tyrosine residues are not required for this internalization pathway. EGF treatment with EGFR, ERK1/2 inhibitors, clathrin inhibitors, mutagenesis of PDZ/SH3 motifs and tyrosine residues, immunofluorescence tracking of Kv1.3 internalization Cellular and Molecular Life Sciences Medium 26542799
2014 Recombinant human Klotho protein enhances Kv1.3 channel abundance and currents in the plasma membrane via its β-glucuronidase activity, as demonstrated in Xenopus oocytes expressing KCNA3 and in Jcam lymphoma cells. Xenopus oocyte expression system with dual electrode voltage clamp, flow cytometry for Kv1.3 protein abundance, β-glucuronidase inhibitor (DSAL) reversal Kidney & Blood Pressure Research Medium 25571875
2005 Rat microglia express Kv1.3 channels that are required for NADPH oxidase-mediated respiratory burst and neurotoxicity; activated microglia kill hippocampal neurons through a process requiring Kv1.3 channel activity in microglia (not neurons), with peroxynitrite as a major neurotoxic mediator; Kv1.3 blockers reduce the respiratory burst but not nitric oxide production, operating independently of p38 MAPK. Transwell co-culture system with separate drug treatment, Kv1.3 channel blockers, LPS/phorbol ester activation, neurotoxicity assays, p38 MAPK activation measurement, respiratory burst assay Journal of Neuroscience High 16079396
2018 Kv1.3 is required for microglial pro-inflammatory (M1-like) activation in vivo; Kv1.3 KO or PAP-1 blockade abolishes LPS-induced IL-1β, TNF-α, IL-6, and iNOS expression in microglia and rescues hippocampal long-term potentiation impaired by LPS-induced neuroinflammation. In vivo intracerebroventricular LPS injection, microglia acute isolation, whole-cell patch-clamp, Kv1.3 KO mice, PAP-1 pharmacological blockade, LTP recording, qPCR for inflammatory mediators Glia High 30043400
2020 Kv1.3 channels contribute to setting resting microglial membrane potential and counteract excessive depolarization produced by ATP-mediated P2X4 receptor activation; Kv1.3 inhibition with ShK-223 dissipates the electrochemical driving force for Ca2+ entry through P2X4, reducing calcium transients and linking Kv1.3 function mechanistically to P2X4 receptor-mediated signaling. Whole-cell voltage- and current-clamp electrophysiology, P2X4 ATP activation, ShK-223 Kv1.3 blockade, qPCR for stimulus-dependent expression patterns in vitro and in vivo Glia High 32525239
2020 β1-integrin binding to VCAM-1 on neurons triggers KV1.3 channel-dependent vesicular glutamate release from Th17 cells via SNARE complex proteins; inhibiting either glutaminase or KV1.3 channels blocks this glutamate secretion pathway. SNARE protein identification in Th17 cells, glutamate secretion assays, KV1.3 channel blockers, glutaminase inhibitor, intrathecal drug delivery in EAE model Journal of Clinical Investigation Medium 31661467
2022 Kv1.3 regulates neutrophil store-operated Ca2+ entry by maintaining membrane potential via K+ efflux; KV1.3 inhibition (PAP-1) or genetic deletion impairs Ca2+ signaling, cellular spreading, adhesion strengthening, crawling under flow, phagocytosis, and neutrophil extravasation in inflamed tissue in vivo. Patch-clamp electrophysiology, intracellular Ca2+ imaging, in vitro adhesion/crawling assays under flow, intravital microscopy in inflamed cremaster muscle, peritoneal inflammation model, KV1.3 KO mice Cardiovascular Research High 33881519
2010 Granzyme B released by activated T cells suppresses neural progenitor cell (NPC) proliferation and neuronal differentiation via a Gi-protein-coupled receptor pathway that decreases cAMP and upregulates Kv1.3 expression; blocking Kv1.3 channel activity or expression with margatoxin reverses GrB-mediated inhibition of NPCs. Co-culture of activated T cells with NPCs, GrB treatment, Gi inhibitor, cAMP measurement, Kv1.3 expression assay, margatoxin treatment, proliferation and differentiation assays Journal of Neuroscience Medium 20371822
2024 Proximity labeling proteomics (TurboID-Kv1.3) in BV-2 microglia revealed that the N-terminus of Kv1.3 mediates trafficking to the cell surface and mitochondria (interacting with NUDC, TIMM50), while the C-terminal PDZ-binding domain mediates interaction with immune signaling proteins (STAT1, TLR2, C3) during LPS-induced inflammation; Kv1.3 blockade reduces interferon-mediated STAT1 activation. TurboID proximity labeling, mass spectrometry, electrophysiology, Western blot, flow cytometry, PDZ-binding domain deletion mutant, LPS activation Molecular & Cellular Proteomics Medium 38936775
2014 Kv1.3-mediated proliferation of human vascular smooth muscle cells operates via MEK/ERK and PLCγ signaling pathways but not via PI3K/mTOR; Kv1.3 blocker anti-proliferative effects are occluded by MEK/ERK and PLCγ inhibitors but not mTOR inhibitors. Pharmacological blockade of Kv1.3 combined with pathway-specific inhibitors (MEK/ERK, PLCγ, PI3K/mTOR), proliferation assays in human coronary artery VSMCs Pflugers Archiv Medium 25208915
2021 Kv1.3-high CNS mononuclear phagocytes in Alzheimer's disease mouse model (5xFAD) originate from microglia (not blood-derived monocytes), as demonstrated by irradiation bone marrow chimerism; Kv1.3 channels regulate membrane potential and early Ca2+ signaling in microglia; in vivo Kv1.3 blockade reduces Aβ burden and promotes a pro-phagocytic gene expression profile. Irradiation bone marrow CD45.1/CD45.2 chimerism, transcriptomic profiling, electrophysiology, ShK-223 in vivo blockade, flow cytometry, gene expression analysis PNAS High 33649184

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proceedings of the National Academy of Sciences of the United States of America 461 17088564
2007 Ubiquitination of serine, threonine, or lysine residues on the cytoplasmic tail can induce ERAD of MHC-I by viral E3 ligase mK3. The Journal of cell biology 233 17502423
2008 Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 191 18818304
2005 Microglia Kv1.3 channels contribute to their ability to kill neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 169 16079396
1996 Tyrosine phosphorylation of the Kv1.3 potassium channel. The Journal of neuroscience : the official journal of the Society for Neuroscience 151 8774427
2012 Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells. EMBO molecular medicine 145 22496117
2003 The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight. Human molecular genetics 130 12588802
2016 Differential Kv1.3, KCa3.1, and Kir2.1 expression in "classically" and "alternatively" activated microglia. Glia 127 27696527
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