| 2022 |
Cryo-EM structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker revealed two distinct inhibitory mechanisms: four nanobody copies bind the voltage-sensing domains and pore domain to induce an inactive pore conformation, while the antibody-toxin fusion docks its toxin domain at the extracellular mouth and inserts a critical lysine into the pore, stabilizing an active pore conformation while blocking ion permeation. |
Cryo-EM structure determination with functional validation |
Nature communications |
High |
35788586
|
| 2008 |
Kv1.3 is present in the inner mitochondrial membrane of lymphocytes. Bax interacts with and functionally inhibits mitochondrial Kv1.3, triggering sequential hyperpolarization, ROS formation, cytochrome c release, and depolarization. Mutation of Bax at K128, corresponding to a conserved lysine in Kv1.3-inhibiting toxins, abrogated Bax effects on both Kv1.3 and mitochondria. Cells lacking Kv1.3 or with siRNA knockdown resisted Bax-induced apoptosis, restored by retransfection with mitochondria-targeted Kv1.3. |
siRNA knockdown, genetic KO, reconstitution with mitochondria-targeted Kv1.3, isolated mitochondria incubation with recombinant Bax/t-Bid, site-directed mutagenesis (BaxK128E) |
Proceedings of the National Academy of Sciences of the United States of America |
High |
18818304
|
| 1997 |
EGF receptor and insulin receptor tyrosine kinases modulate Kv1.3 current. EGF treatment suppresses Kv1.3 current and speeds C-type inactivation via tyrosine phosphorylation; mutation of tyrosine at position 479 to phenylalanine blocks the EGF-mediated current suppression. Insulin treatment also inhibits Kv1.3 current but does not affect C-type inactivation kinetics, indicating distinct mechanisms for the two receptor tyrosine kinases. |
Whole-cell patch clamp in HEK293 co-expression system, site-directed mutagenesis (Y479F), tyrosine kinase inhibitor (erbstatin), receptor-blocking antibody |
The Journal of general physiology |
High |
9348331
|
| 2006 |
Kv1.3 and Kv1.5 form functional heterotetramers in macrophages. Co-expression shifts half-activation voltage and alters pharmacological sensitivity. Both proteins co-immunoprecipitate and FRET studies confirm heteroteramer formation. TNF-α activation increases Kv1.3 without changing Kv1.5, producing a hyperpolarized shift consistent with increased Kv1.3 content. |
Co-immunoprecipitation, FRET, co-expression in HEK293 and Xenopus oocytes, whole-cell patch clamp, pharmacological profiling |
The Journal of biological chemistry |
High |
17038323
|
| 2006 |
In activated effector memory T cells (TEM), Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56(lck), and CD4. Kv1.3 inhibitors suppress Ca2+-signaling, cytokine production, and proliferation of TEM cells at pharmacologically relevant concentrations. |
Immunofluorescence/confocal microscopy, electrophysiology, Ca2+ signaling assays, cytokine/proliferation assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
17088564
|
| 2009 |
KCNE4, but not KCNE2, functions as an inhibitory partner of Kv1.3 in leukocytes. KCNE4 decreases Kv1.3 current density, slows activation, accelerates inactivation, retains Kv1.3 in the ER, and impairs targeting to lipid raft microdomains, reducing cell surface channel number. |
Co-expression, whole-cell patch clamp, confocal co-localization, surface expression assays, lipid raft fractionation |
Journal of cell science |
High |
19773357
|
| 2003 |
KCNE4 beta-subunit has a drastic inhibitory effect on Kv1.3 currents expressed in both Xenopus oocytes and HEK293 cells. KCNE4 does not inhibit Kv1.2, Kv1.4, Kv1.5, or Kv4.3 homomeric channels but reduces current through Kv1.1/Kv1.2 and Kv1.2/Kv1.3 heteromeric complexes. |
Heterologous expression in Xenopus oocytes and HEK293 cells, whole-cell patch clamp, confocal microscopy, Western blot |
Biophysical journal |
High |
12944270
|
| 2016 |
The C-terminal domain of Kv1.3 is necessary and sufficient for interaction with KCNE4. KCNE4 retains Kv1.3 intracellularly via two independent mechanisms: masking the YMVIEE C-terminal surface targeting sequence, and an ER retention motif within KCNE4 itself. |
Co-immunoprecipitation, chimeric/truncation constructs, surface expression assays, confocal microscopy |
Journal of cell science |
Medium |
27802162
|
| 2000 |
During ER biogenesis of Kv1.3, transmembrane segments S1, S2, S4, and S5 exhibit signal anchor or membrane integration activity; S3 and S6 fail to integrate independently. The N-terminal T1 domain prevents S1 from initiating translocation, making S2 the likely initial signal sequence. Multiple topogenic determinants cooperate during Kv1.3 assembly. |
Protease protection assays, glycosylation site insertion, carbonate extraction, cell-free translation/translocation system |
Biochemistry |
High |
10651649
|
| 1997 |
PKC activation upregulates native Kv1.3 channel activity in human T lymphocytes, shifting voltage dependence of activation and inactivation and increasing window current ~270%. PKC inhibition reduces current. PKC-dependent phosphorylation acts as a master switch that overrides PKA-mediated upregulation. |
Whole-cell patch clamp in primary human T lymphocytes, pharmacological PKC activators/inhibitors, pseudosubstrate peptides, calphostin C dose-response |
The Journal of membrane biology |
Medium |
9070466
|
| 1997 |
PKA activation increases native Kv1.3 conductance in human T lymphocytes by ~60% and shifts inactivation voltage, increasing window current. Phosphatase inhibition (okadaic acid) similarly increases conductance. PKC and PKA effects are not simply additive; PKC-dependent phosphorylation dominates regulation. |
Whole-cell patch clamp, pharmacological PKA activators/inhibitors, phosphatase inhibitors in primary human T lymphocytes |
The American journal of physiology |
Medium |
9277360
|
| 2004 |
Gene-targeted deletion of Kv1.3 in mice alters potassium current kinetics in olfactory bulb mitral cells (slow inactivation, modified voltage dependence, dampened C-type inactivation), abolishes modulation by receptor tyrosine kinase activators, and increases expression of scaffolding proteins that normally regulate the channel through protein-protein interactions. KO mice have smaller, more numerous olfactory glomeruli and dramatically lower olfactory detection thresholds. |
Gene-targeted KO mice, whole-cell patch clamp, behavioral olfaction tests, immunohistochemistry, Western blot |
Neuron |
High |
14766178
|
| 2003 |
Kv1.3-deficient mouse thymocytes lack voltage-dependent K+ current, but develop a ~50-fold increased chloride current as a compensatory mechanism. Despite loss of Kv1.3, no defects in lymphocyte numbers, thymocyte apoptosis, or T cell proliferation are observed in mice, likely due to this chloride current compensation. |
Genetic KO mice (Kv1.3-/-), whole-cell patch clamp, flow cytometry, proliferation assays |
The Journal of biological chemistry |
High |
12878608
|
| 2011 |
KCNE2 forms functional potassium channels with KCNA3 (Kv1.3) in the choroid plexus epithelium apical membrane. Targeted Kcne2 deletion alters KCNA3 trafficking polarity, hyperpolarizes the choroid plexus membrane by ~9 mV, and increases CSF chloride concentration by 14%. |
Kcne2 KO mice, patch clamp, immunohistochemistry, ion-selective electrodes for CSF composition, pharmacological blockers (margatoxin) |
FASEB journal |
High |
21859894
|
| 2016 |
Cereblon (CRBN) epigenetically represses Kcna3 (Kv1.3) transcription by directly binding conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. In the absence of CRBN, Kv1.3 expression is derepressed, increasing K+ flux, Ca2+-mediated signaling, and CD4+ T cell hyperactivation. |
Crbn KO mice, ChIP assay, Ca2+ flux assays, cytokine production, EAE model, CD4+ T cell functional assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
27439875
|
| 2012 |
Kv1.3 promotes cell proliferation in vascular smooth muscle cells through an ion-flux independent mechanism requiring voltage-dependent conformational change. A poreless Kv1.3 mutant retains pro-proliferative activity, but abolishing voltage-dependent gating eliminates this effect. |
Heterologous expression in HEK cells, poreless mutant and gating-deficient mutant channels, proliferation assays, electrophysiology |
Arteriosclerosis, thrombosis, and vascular biology |
High |
22383699
|
| 2015 |
Kv1.3 C-terminal residues Tyr-447 and Ser-459 are required for Kv1.3-induced cell proliferation. Voltage-dependent channel gating induces MEK-ERK1/2-dependent phosphorylation of Tyr-447, providing a signaling mechanism linking channel conformational change to proliferation independently of ion conduction. |
Chimeric Kv1.3-Kv1.5 channels, point mutants, GFP/cherry fusion proteins, immunocytochemistry, electrophysiology, MEK inhibitors, proliferation assays in HEK293 cells |
The Journal of biological chemistry |
High |
26655221
|
| 2017 |
PKC activation triggers ubiquitination of Kv1.3 by the E3 ubiquitin ligase Nedd4-2, leading to clathrin-mediated endocytosis and lysosomal degradation, thereby reducing surface channel expression. PSD-95 (MAGUK family) recruits Kv1.3 to lipid raft microdomains and protects it from ubiquitination and endocytosis. Adenosine stimulates PKC-mediated Kv1.3 downregulation as an immunosuppressive mechanism. |
Co-immunoprecipitation, ubiquitination assays, clathrin inhibitors, lysosomal pathway inhibitors, flow cytometry, confocal microscopy in leukocytes |
Scientific reports |
Medium |
28186199
|
| 2015 |
EGF receptor activation triggers ERK1/2-mediated threonine phosphorylation of Kv1.3, causing clathrin-dependent endocytosis and lysosomal degradation of the channel. PDZ and SH3 interaction motifs and tyrosine residues are not required for this mechanism; the ERK1/2-mediated threonine phosphorylation is the critical step. |
Endocytosis assays, clathrin inhibitors, site-directed mutants (PDZ, SH3, tyrosine residues), ERK inhibitors, confocal microscopy |
Cellular and molecular life sciences |
Medium |
26542799
|
| 2016 |
Kv1.3 is targeted to caveolar lipid raft microdomains through a highly hydrophobic caveolin-binding domain (FQRQVWLLF) in the intracellular N-terminus that interacts with caveolin-1. Mutations or associations altering this domain impair caveolin recognition and change channel surface localization. |
Co-immunoprecipitation, co-localization, mutagenesis of caveolin-binding domain, cholesterol depletion, lipid raft fractionation |
Scientific reports |
Medium |
26931497
|
| 2021 |
Disruption of the Kv1.3–caveolin-1 interaction (via a caveolin-binding domain mutant) causes Kv1.3 to accumulate in mitochondria rather than the plasma membrane, severely affecting mitochondrial physiology and reducing cell survival, revealing a mitochondrial caveolin-Kv1.3 axis that modulates pro-apoptotic signaling. |
Caveolin-binding domain mutant expression, subcellular fractionation, mitochondrial physiology assays, cell survival assays in mammalian cells |
eLife |
Medium |
34196606
|
| 2022 |
Kv1.3 uses the TIM23 complex for translocation to the inner mitochondrial membrane via an unconventional mechanism (no defined N-terminal presequence; transmembrane domains cooperatively mediate targeting). The cytosolic HSP70/HSP90 chaperone complex is a key regulator of the mitochondrial import process. |
Mitochondrial import assays, TIM23 complex interaction studies, HSP70/HSP90 inhibition, subcellular fractionation, domain-deletion constructs |
Frontiers in oncology |
Medium |
35402277
|
| 2012 |
N-glycosylation of Kv1.3 at position N229 in the S1-S2 extracellular linker promotes cell surface expression; blocking N-glycosylation reduces surface protein levels by ~49% and surface conductance by ~46%. GlcNAc supplementation increases surface Kv1.3 half-life by decreasing internalization. |
N-glycosylation site mutagenesis, surface biotinylation, patch clamp, monosaccharide supplementation experiments |
The FEBS journal |
Medium |
22613618
|
| 2008 |
Kv1.3 and Kv1.5 form heterotetramers in macrophages that differ in surface localization compared to Kv1.3 homotetramers; Kv1.5 association modifies Kv1.3 trafficking and reduces its caveolin-associated raft targeting. FRAP analysis shows higher lateral mobility for Kv1.3/Kv1.5 heteromers than Kv1.3 homotetramers. |
FRET, co-immunoprecipitation, FRAP, cholesterol depletion, caveolae co-localization, confocal microscopy in HEK cells and macrophages |
The Journal of biological chemistry |
Medium |
18218624
|
| 2020 |
The kinase Fyn directly binds to and posttranslationally modifies Kv1.3, modulating its channel activity. Fyn also transcriptionally upregulates Kv1.3 in microglia in response to aggregated α-synuclein. Fyn-dependent regulation of Kv1.3 amplifies neuroinflammatory responses in Parkinson's disease models. |
Duolink proximity ligation assay, patch-clamp electrophysiology, Kv1.3-KO primary microglia, PAP-1 pharmacological inhibition, animal models of PD |
The Journal of clinical investigation |
Medium |
32597830
|
| 1999 |
In hippocampal microglia, there is a switch from Kv1.5-like current (in non-proliferating cells) to Kv1.3-like current (in proliferating cells) during culture, accompanied by redistribution of Kv1.5 protein away from and Kv1.3 protein to the cell surface. Pharmacological inhibition correlated with the Kv channel type expressed indicates that Kv1.3 current is required for microglial proliferation. |
Tissue printing from brain slices, whole-cell patch clamp, immunocytochemistry, K+ channel blockers, proliferation assays |
The Journal of neuroscience |
Medium |
10594052
|
| 2005 |
Kv1.3 channel activity in activated microglia is required for microglial-mediated neurotoxicity toward hippocampal neurons. The neurotoxic mechanism involves peroxynitrite production: Kv1.3 blockers reduce the NADPH oxidase-dependent respiratory burst (superoxide), without affecting nitric oxide production, thereby limiting peroxynitrite formation. Kv1.3 channel activity in this pathway is distinct from p38 MAPK used by minocycline. |
Transwell co-culture, LPS/phorbol ester activation, Kv1.3 channel blockers, reactive oxygen species measurement, NO measurement, p38 MAPK inhibitor comparison |
The Journal of neuroscience |
Medium |
16079396
|
| 2021 |
Kv1.3 channels increase mitochondrial oxidative phosphorylation independently of redox balance, mitochondrial membrane potential, or calcium signaling. This Kv1.3-induced respiration increases ROS production, which drives proliferation. The mechanism requires an intact voltage sensor and C-terminal ERK1/2 phosphorylation site but is channel pore independent (non-conducting mechanism). |
High-resolution respirometry, selective Kv1.3 channel mutation (poreless, voltage sensor, ERK site), ROS measurement, ROS scavenging, proliferation assays |
Cell death & disease |
Medium |
33828089
|
| 2009 |
Kv1.3 is present in the inner mitochondrial membrane of lymphocytes and also cancer cells (PC3, MCF-7). Recombinant Kv1.3 pre-incubated with Bax prevents Bax-induced mitochondrial effects, further establishing the Kv1.3-Bax interaction at the mitochondria. |
Mitochondrial fractionation, Western blot, recombinant protein incubation, mitochondrial functional assays |
Biochimica et biophysica acta |
Medium |
20114030
|
| 2010 |
Kv1.3 channels contribute to cell-autonomous apoptotic death of retinal ganglion cells after optic nerve transection. siRNA knockdown of Kv1.3 in vivo reduced expression of proapoptotic genes caspase-3, caspase-9, and Bad, distinct from the Kv1.1-depletion effect (which increased antiapoptotic Bcl-XL). |
In vivo optic nerve transection model, siRNA delivered via cut optic nerve, Kv1.3 blocker injection, qRT-PCR, immunohistochemistry, RGC survival counts |
Cell death and differentiation |
Medium |
19696788
|
| 2009 |
Kv1.3 premature exit from the immunological synapse in SLE T cells correlates with sustained Ca2+ influx and T cell hyperactivation. In normal T cells, Kv1.3 remains at the IS during termination of Ca2+ influx, suggesting that Kv1.3 trafficking regulates Ca2+ signaling duration. |
Two-photon microscopy, immunofluorescence, Ca2+ imaging during IS formation in primary T cells from SLE patients vs. controls |
Cell calcium |
Medium |
19959227
|
| 2015 |
Kv1.3 is expressed in the nuclei of multiple cancer cell lines and human brain tissue. Nuclear Kv1.3 is functional (margatoxin induces nuclear membrane hyperpolarization in a Kv1.3-dependent manner). Nuclear Kv1.3 forms a complex with upstream binding factor 1 (UBF1) and its blockade induces CREB and c-Fos phosphorylation/activation. Sp1 transcription factor binds the Kv1.3 gene promoter and regulates its nuclear expression. |
Subcellular fractionation, Western blot, nuclear electrophysiology, siRNA knockdown, ChIP assay, co-immunoprecipitation |
The Journal of biological chemistry |
Medium |
25829491
|
| 2020 |
Kv1.3 channel activity in Th17 cells is required for β1-integrin/VCAM-1-triggered vesicular glutamate release that damages neurons. Blocking Kv1.3 with a specific channel blocker prevents glutamate secretion downstream of β1-integrin signaling. |
KV1.3 channel blocker (in vitro and intrathecal), glutamate release assays, Ca2+ imaging, SNARE protein identification, VCAM-1 stimulation assays |
The Journal of clinical investigation |
Medium |
31661467
|
| 2003 |
Kv1.1 and Kv1.3 channels mediate the delayed-rectifying K+ conductance at the apical membrane of rat choroid plexus epithelial cells. 5-HT inhibits this conductance via 5-HT2C receptors activating PKC, which inhibits Kv1.1 and Kv1.3 channels. |
Whole-cell patch clamp, selective channel blockers (dendrotoxin-K, margatoxin), Western blot, immunocytochemistry, 5-HT2C receptor antagonist, PKC inhibitor |
American journal of physiology. Cell physiology |
Medium |
14602579
|
| 1999 |
Kv1.3 channels block membrane potential and calcium influx in human T cells. Correolide blocks Kv1.3 channels in T cells, inhibiting anti-CD3-induced calcium elevation, IL-2 production, and T cell proliferation, demonstrating that Kv1.3 controls Ca2+-dependent T cell activation. |
Electrophysiology, Ca2+ flux assays, cytokine ELISA, proliferation assays, in vivo delayed-type hypersensitivity in miniswine |
Cellular immunology |
Medium |
10607427
|
| 2024 |
Proximity labeling proteomics (TurboID fused to Kv1.3) in microglia revealed that the N-terminus of Kv1.3 is responsible for trafficking to cell surface and mitochondria (interactors include NUDC, TIMM50), while the C-terminus interacts with immune signaling proteins (STAT1, TLR2, C3) during LPS-induced inflammation. A C-terminal PDZ-binding domain mediates 70 protein interactions. Kv1.3 functionally couples to STAT1 interferon-mediated signaling (confirmed by channel blockade). |
TurboID proximity labeling, mass spectrometry, electrophysiology, Western blot, flow cytometry, domain-specific constructs |
Molecular & cellular proteomics |
Medium |
38936775
|
| 2018 |
Kv1.3 is localized to caveolae in adipocytes via interaction with caveolin-1. Insulin-dependent phosphorylation of Kv1.3 occurs during insulin signaling. In caveolin-1-deficient adipocytes, Kv1.3 is displaced from caveolar rafts and shows impaired insulin-dependent phosphorylation, indicating caveolar targeting is required for proper insulin signaling through Kv1.3. |
Caveolin-1 KO adipocyte cell line, lipid raft fractionation, co-immunoprecipitation, phosphorylation assays, glucose uptake assays |
Cellular and molecular life sciences |
Medium |
29947924
|
| 2016 |
Kv1.3 channel activity contributes to both NADPH oxidase-dependent ROS production and proliferation in M1-like microglia. Both Kv1.3 and KCa3.1 blockers inhibit pro-inflammatory cytokine production and iNOS/COX2 expression in LPS/IFN-γ-activated (M1) microglia. |
Whole-cell patch clamp, quantitative PCR, immunohistochemistry, pharmacological blockers (PAP-1, ShK-186, TRAM-34) in mouse neonatal microglia |
Glia |
Medium |
27696527
|
| 1996 |
Kv1.3 subunit assembly in T lymphocytes is a random process forming tetramers. Once expressed in the plasma membrane, tetramers do not dissociate and reassemble. A truncated Kv1.3 containing only the N-terminus and first two transmembrane segments can suppress endogenous Kv1.3 current by forming non-functional heterotetramers. |
Kinetic analysis of C-type inactivation of heterotetrameric channels, heterologous expression in Jurkat cells, dominant-negative suppression assays |
The Journal of general physiology |
Medium |
8868051
|
| 2008 |
Kv1.3 channels are expressed in postganglionic sympathetic neurons at cell bodies, processes, and sympathetic neurovascular junctions. Margatoxin-sensitive Kv1.3 current depolarizes resting membrane potential and decreases action potential latency. Kv1.3 modulates nicotinic ACh receptor-induced norepinephrine release; muscarinic receptor activation with bethanechol suppresses Kv1.3 current. |
RT-PCR, immunoblot, immunohistochemistry, whole-cell patch clamp, margatoxin pharmacology, norepinephrine release assay |
American journal of physiology. Regulatory, integrative and comparative physiology |
Medium |
18614767
|