Affinage

KCNC3

Voltage-gated potassium channel KCNC3 · UniProt Q14003

Length
757 aa
Mass
80.6 kDa
Annotated
2026-06-10
51 papers in source corpus 28 papers cited in narrative 27 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

KCNC3 encodes Kv3.3, a voltage-gated Shaw-type potassium channel that drives fast action-potential repolarization and high-frequency firing in cerebellar Purkinje cells and auditory brainstem neurons (PMID:18256249, PMID:32246836, PMID:15217387). Its N-terminal domain mediates N-type inactivation, which is removed by deletion of the first 78 residues and modulated by PKC phosphorylation at N-terminal serines 3 and 9; inactivation rate is further tuned by translational start-site selection through the upstream Kozak context (PMID:12923191, PMID:18539595). The cytoplasmic C-terminus is a multifunctional hub: a proline-rich segment binds the actin-regulatory protein Hax-1 to recruit Arp2/3 and build a cortical actin network that suppresses rapid inactivation (PMID:26997484), a distinct C-terminal targeting sequence directs the channel to distal dendrites (PMID:16354911), and the channel is anchored to the β3-spectrin cytoskeleton through Ankyrin-R and targeted by MAP6 binding to the N-terminal T1 tetramer (PMID:34785580, PMID:42069089). Beyond conducting current, Kv3.3 binds and stimulates the kinase TBK1, which controls Hax-1 trafficking into multivesicular bodies and governs neuronal survival (PMID:33741962). Functionally, somatic Kv3.3 supports complex-spike spikelets while dendritic channels oppose Ca2+ spike initiation, and presynaptic Kv3.3 shapes transmitter release and short-term plasticity at the calyx of Held (PMID:18256249, PMID:20357073, PMID:35510987). Disease-causing mutations act through several routes: dominant-negative, non-conducting voltage-sensor mutations (R420H, R423H) with Golgi/endosomal retention and aberrant EGFR trafficking (PMID:16501573, PMID:25152487, PMID:28467418); gating alterations with slowed deactivation (F448L, R423H) (PMID:16501573, PMID:19953606, PMID:22289912); and a C-terminal mutation (G592R) that overactivates TBK1 to degrade Hax-1 and trigger Purkinje cell death (PMID:33741962). Mutant-induced hyperexcitability drives Ca2+-dependent Purkinje cell degeneration, rescuable by blocking P/Q-type Ca2+ channels or by Kcnc3-targeting antisense oligonucleotides (PMID:24218544, PMID:34820911, PMID:32644043).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1992 Medium

    Establishing the gene structure and chromosomal location of KCNC3 provided the molecular foundation for studying this channel, defining its modular exon organization separating the N-terminal region from the transmembrane core.

    Evidence Genomic and cDNA cloning with chromosomal mapping

    PMID:1740329

    Open questions at the time
    • No functional or electrophysiological characterization
    • Channel properties not yet defined
  2. 2003 High

    It was unknown how Kv3.3 inactivation is controlled; mutagenesis showed N-type inactivation is governed by the N-terminal domain and tuned by translational start-site usage, revealing a layer of regulation set before channel function.

    Evidence N-terminal and Kozak deletion mutagenesis with electrophysiology in CHO and HEK cells

    PMID:12923191

    Open questions at the time
    • Physiological role of start-site selection in neurons not established
    • Upstream signals controlling inactivation not yet identified
  3. 2003 High

    The contribution of Kv3 channels to synaptic transmission was unclear; double-knockout work showed Kv3.1/Kv3.3 loss broadens presynaptic action potentials and elevates Ca2+ influx, altering short-term plasticity at parallel fiber synapses.

    Evidence Kv3.1/Kv3.3 double-knockout mice with field recordings and plasticity assays

    PMID:12930807

    Open questions at the time
    • Cannot separate Kv3.3-specific from Kv3.1 contribution
    • Does not address postsynaptic roles
  4. 2004 High

    The in vivo necessity of Kv3.3 was undefined; single-knockout mice established that Kv3.3 is essential for Purkinje cell repolarization and olivocerebellar tremor generation, localizing the protein to somata, proximal dendrites, and DCN-projecting axons.

    Evidence Kv3.3 single-knockout mice with harmaline tremor assay, electrophysiology, and immunohistochemistry

    PMID:15217387

    Open questions at the time
    • Molecular partners not identified
    • Mechanism of dendritic versus somatic function not resolved
  5. 2005 High

    How Kv3.3 achieves its subcellular distribution was unknown; in vivo retargeting showed a C-terminal sequence with a PDZ-binding motif is necessary and sufficient for distal dendritic localization, distinguishing it from Kv3.1.

    Evidence In vivo viral expression and C-terminal swap/deletion mutagenesis in teleost ortholog

    PMID:16354911

    Open questions at the time
    • PDZ binding partner not identified
    • Cross-species relevance to mammalian channel inferred
  6. 2006 High

    The link between KCNC3 and human ataxia was unestablished; oocyte expression of disease mutations showed R420H is dominant-negative and non-conducting while F448L alters gating, defining the channel basis of dominant cerebellar ataxia.

    Evidence Xenopus oocyte expression with voltage-clamp electrophysiology of two patient mutations

    PMID:16501573

    Open questions at the time
    • Trafficking fate of mutant channels not yet examined
    • Cellular consequence in neurons not addressed
  7. 2008 High

    Three studies dissected the cell-autonomous and modulatory roles of Kv3.3: PKC phosphorylation of N-terminal serines removes inactivation and boosts current, somatic Kv3 activity enables complex-spike spikelets coordinated with resurgent Na+ channels, and Purkinje-cell-restricted reexpression rescues coordination but not motor learning.

    Evidence PKC pharmacology with serine mutagenesis; slice electrophysiology and modeling in KO mice; Purkinje-cell-specific transgenic rescue

    PMID:18256249 PMID:18448641 PMID:18539595

    Open questions at the time
    • Why motor learning is not rescued unresolved
    • PKC kinase upstream of Kv3.3 in vivo not identified
  8. 2009 High

    The circuit basis of movement control was unclear; genetic epistasis showed Purkinje-cell Kv3.3 rescue requires intact Kv3.1 in deep cerebellar nucleus neurons, partitioning movement velocity and gait patterning between cell types.

    Evidence Compound Kcnc1/Kcnc3 mutant mice with DCN recordings and gait analysis

    PMID:20016089

    Open questions at the time
    • Molecular interaction between the two channels not implied
    • Downstream motor pathways not mapped
  9. 2010 High

    The dendritic function of Kv3.3 was undefined; imaging in KO mice showed dendritic Kv3.3 opposes Ca2+ spike initiation and limits distal dendritic Ca2+ influx during climbing fiber activation.

    Evidence Two-photon Ca2+ imaging, local pharmacology, and voltage clamp in Kv3.3 KO mice

    PMID:20357073

    Open questions at the time
    • Link between dendritic Ca2+ control and survival not yet made
    • Channel partners in dendrites unknown
  10. 2010 High

    It was unclear whether all voltage-sensor mutations behave identically; subunit-mixing showed R423H is dominant-negative with hyperpolarized activation and slowed gating resembling F448L, distinct from R420H, refining genotype-phenotype relationships.

    Evidence Xenopus oocyte expression of heterotetrameric wild-type/mutant mixtures

    PMID:19953606 PMID:22289912

    Open questions at the time
    • Cellular trafficking consequences not addressed here
    • Structural basis of differential gating not resolved
  11. 2013 High

    How mutant Kv3.3 kills neurons was unknown; lentiviral R424H expression in Purkinje cells caused hyperexcitability, elevated Ca2+, impaired dendrites, and selective cell death rescuable by P/Q-type Ca2+ channel block, linking gain-of-excitability to Ca2+-dependent degeneration.

    Evidence Lentiviral expression in cerebellar cultures with patch clamp, Ca2+ imaging, and pharmacological rescue

    PMID:24218544

    Open questions at the time
    • Apoptotic effectors not identified
    • In vivo confirmation in intact cerebellum not provided here
  12. 2014 High

    The fate of the dominant-negative R420H protein was undefined; biochemistry showed it has reduced complex glycans, is largely retained in the Golgi with only ~24% surface expression, and distorts Golgi morphology.

    Evidence Surface biotinylation, EM, IHC, and glycosylation analysis

    PMID:25152487

    Open questions at the time
    • Mechanism of Golgi retention not defined
    • Consequence for trafficking of other proteins not examined
  13. 2016 High

    The molecular basis of inactivation resistance was unknown; Co-IP and functional assays revealed the C-terminal proline-rich domain binds Hax-1 to recruit Arp2/3 and build a cortical actin network that prevents rapid inactivation, with a disease mutation disrupting this assembly.

    Evidence Co-immunoprecipitation, actin assembly assays, cytochalasin D, electrophysiology, and imaging in stem cell-derived neurons

    PMID:26997484

    Open questions at the time
    • Regulation of Hax-1 recruitment by signaling not yet linked
    • Stoichiometry of channel-actin coupling unresolved
  14. 2016 Low

    A possible non-neuronal role was probed; Kv3.3 knockdown in K562 cells enhanced erythroid differentiation and altered p38/CREB/c-fos signaling and integrin β3-mediated adhesion.

    Evidence siRNA knockdown with flow cytometry, Western blot, and adhesion assays in K562 cells

    PMID:26849432

    Open questions at the time
    • Single cell line, single method class with limited mechanistic depth
    • Relevance to channel conductance not established
    • Not independently confirmed
  15. 2017 Medium

    Whether mutant Kv3.3 affects other membrane proteins was untested; R423H caused intracellular retention and altered glycosylation and, across Drosophila and mammalian cells, disrupted EGFR trafficking, linking channel mutation to broader membrane protein handling.

    Evidence Mammalian cell expression, electrophysiology, Drosophila eye rescue, and EGFR immunofluorescence

    PMID:28467418

    Open questions at the time
    • EGFR mechanism inferred across species
    • Direct physical interaction with EGFR not shown
  16. 2018 Medium

    The specificity of actin-dependent inactivation control was tested; C-terminal proline deletions slowed inactivation and reduced sensitivity to actin depolymerization while leaving trafficking normal, confirming the proline-rich region in actin-mediated gating.

    Evidence Mammalian cell electrophysiology with latrunculin B and trafficking assays

    PMID:29949095

    Open questions at the time
    • Single lab electrophysiology
    • In vivo consequence of this variant not established
  17. 2020 High

    Two studies defined cell-type-specific and age-dependent roles: Kv3.3 is essential and non-redundant for LSO neuron repolarization (interchangeable with Kv3.1 only in MNTB), and in zebrafish infant-onset (R423H) versus adult-onset (R420H) mutations produce divergent excitability and survival outcomes, with reduced excitability improving Purkinje cell survival.

    Evidence Kv3.3 KO auditory brainstem electrophysiology; zebrafish in vivo electrophysiology, imaging, and Ca2+ channel blocker rescue

    PMID:32246836 PMID:32644043

    Open questions at the time
    • Molecular basis of age-dependent vulnerability not defined
    • Whether human mutations follow the same trajectory not shown
  18. 2021 High

    Three studies revealed Kv3.3's non-conducting roles and cytoskeletal anchoring: the channel binds and stimulates TBK1 to control Hax-1 trafficking and survival (G592R overactivating this pathway), Ankyrin-R links Kv3.3 to β3 spectrin to maintain its membrane levels, and Kcnc3-targeting ASOs reversed TBK1/Hax-1 disruption and motor deficits in G592R mice.

    Evidence Biochemical binding and trafficking assays; Co-IP with conditional Ank1 knockout mice; intracerebroventricular ASO with Western blot and rotarod

    PMID:33741962 PMID:34785580 PMID:34820911

    Open questions at the time
    • Structural basis of TBK1 stimulation by the channel unresolved
    • How channel activity is mechanistically coupled to kinase stimulation not fully defined
  19. 2022 High

    Two studies extended the functional and presynaptic roles: presynaptic Kv3.3 (not Kv3.1) sets calyx of Held AP duration, release probability, and auditory signal fidelity, and a voltage-sensor mutation (G434V) abolishing conductance without affecting trafficking causes reduced firing and spatial learning deficits.

    Evidence Kv3.3 KO presynaptic patch clamp, in vivo auditory recordings, and modeling; ENU/CRISPR G434V knock-in mice with electrophysiology and behavior

    PMID:35510987 PMID:35881790

    Open questions at the time
    • Cognitive circuit basis of spatial learning deficit not mapped
    • Presynaptic anchoring partners not identified
  20. 2024 Medium

    It was unknown whether KCNC3 dose alone causes disease; a Kozak variant (c.-6C>A) was shown to increase translation and Kv3.3 protein without altering transcription, demonstrating that elevated channel expression can cause ataxia.

    Evidence Luciferase reporters, qPCR, methylation analysis, and patient variant identification

    PMID:39596509

    Open questions at the time
    • Neuronal consequence of overexpression not directly tested
    • Single lab translational evidence
  21. 2026 Medium

    A new cytoskeletal targeting mechanism was defined; MAP6 directly binds the Kv3.3 N-terminal T1 tetramer via its Mn modules to regulate axon-dendrite targeting, with MAP6 loss reducing Kv3.3 and Cav2.1 levels and Purkinje burst firing.

    Evidence MAP6 KO mice, shRNA knockdown, direct T1-tetramer binding assay, immunofluorescence, and electrophysiology

    PMID:42069089

    Open questions at the time
    • Single study without reciprocal validation in human cells
    • Relationship between MAP6 and the C-terminal targeting sequence unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Kv3.3 mechanistically couples its conductance to TBK1 kinase stimulation, and how the multiple cytoskeletal anchoring systems (Hax-1/Arp2/3, Ankyrin-R/spectrin, MAP6) are integrated to control localization, gating, and survival, remains unresolved.
  • No structural model linking channel gating to TBK1 activation
  • Integration of distinct cytoskeletal partners not reconciled
  • Human cell validation of survival pathway limited

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9609507 Protein localization 3
Partners
ANK1EGFRHAX1MAP6SPTBN2TBK1
Complex memberships
spectrin-based membrane skeleton

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 KCNC3(R420H), located in the voltage-sensing domain, produced no channel activity when expressed alone and exerted a dominant-negative effect when co-expressed with wild-type Kv3.3 in Xenopus oocytes. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing (approximately 7-fold slowing of deactivation). Xenopus laevis oocyte expression system with electrophysiology (voltage clamp) Nature genetics High 16501573
2003 Kv3.3 channels undergo N-type inactivation mediated by the N-terminal domain; removal of the first 78 amino acids produces non-inactivating currents. The rate of inactivation depends critically on translational start-site usage (Kozak context), with weak Kozak sequence leading to translation initiation at a downstream methionine, bypassing the N-terminal inactivation domain. Expression in CHO and HEK cells; N-terminal deletion mutagenesis; Kozak sequence mutagenesis; electrophysiology The Journal of biological chemistry High 12923191
2008 Protein kinase C (PKC) activation increases Kv3.3 current amplitude and removes N-type inactivation. The N-terminal serines at positions 3 and 9 are identified as potential PKC phosphorylation sites by mutagenesis. Elimination of the first 78 amino acids of the N-terminus produced non-inactivating currents, confirming that PKC modulates N-type inactivation. Expression in mammalian cell line and Xenopus oocytes; PKC activators/inhibitor peptide; N-terminal deletion and serine-to-alanine mutagenesis; electrophysiology The Journal of biological chemistry High 18539595
2016 The cytoplasmic C-terminus of Kv3.3 contains a proline-rich domain that binds Hax-1 (an anti-apoptotic actin-regulatory protein), which in turn recruits Arp2/3 to the plasma membrane, forming a stable cortical actin network resistant to cytochalasin D. This actin network prevents rapid N-type inactivation during short depolarizations. A disease-causing mutation within the proline-rich domain impairs Arp2/3 recruitment, causing actin veil deficiency in stem cell-derived neurons. Co-immunoprecipitation; actin assembly assays; cytochalasin D treatment; electrophysiology; imaging of stem cell-derived neurons; mutagenesis Cell High 26997484
2021 Kv3.3 channels bind and stimulate Tank Binding Kinase 1 (TBK1), an enzyme controlling trafficking of membrane proteins into multivesicular bodies. A disease-causing mutation (G592R) greatly increases TBK1 stimulation. TBK1 activity is required for binding of Kv3.3 to its auxiliary subunit Hax-1. Overactivation of TBK1 by mutant channel leads to Hax-1 accumulation in multivesicular bodies/lysosomes, exosome release, caspase activation, and increased neuronal cell death. Biochemical binding assays; trafficking assays; multivesicular body/lysosome localization; caspase activation assays; mouse cerebellar tissue analysis Nature communications High 33741962
2021 Ankyrin-R (AnkR) physically interacts with Kv3.3 and with β3 spectrin, linking Kv3.3 to the spectrin-based cytoskeleton in Purkinje neurons. Loss of AnkR reduces somatic membrane levels of both β3 spectrin and Kv3.3 in Purkinje neurons, causing progressive neurodegeneration and ataxia. Co-immunoprecipitation; conditional knockout mice (Ank1 floxed × Nestin-Cre and Pcp2-Cre); immunofluorescence; behavioral analysis The Journal of neuroscience High 34785580
2005 The C-terminal domain of Kv3.3 (AptKv3.3 teleost ortholog) contains a targeting sequence sufficient to direct channels to distal dendrites, including a predicted PDZ-binding motif. In vivo viral injection-based retargeting showed that this C-terminal domain is necessary and sufficient for dendritic localization, distinguishing Kv3.3 from Kv3.1 which localizes to soma and proximal dendrites. In vivo viral injection of recombinant channels; immunohistochemistry; deletion/swap mutagenesis of C-terminal domain The Journal of neuroscience High 16354911
2008 Kv3.3 channels at the Purkinje cell soma (not dendrites) are required for generation of repetitive spikelets of the complex spike. Somatic Kv3 activity, coordinated with resurgent Na+ channels, limits Na+ channel inactivation and enables rapid repetitive firing. Kv3.3 knockout mice produce altered complex spikes both in vitro and in vivo. Acute slice electrophysiology; dual somatic-dendritic recordings; Kv3.3 knockout mice; pharmacology; computational modeling of Na+ currents The Journal of neuroscience High 18256249
2008 Purkinje-cell-restricted reexpression of Kv3.3 in Kcnc3-null mice rescued motor coordination (lateral deviation, beam slips) and restored complex spike spikelets and simple spike brevity, but did not restore motor learning. This established Kv3.3 function specifically in Purkinje cells as the cellular basis of coordination deficits. Transgenic rescue (Purkinje-cell-specific Kv3.3 reexpression in Kcnc3-null mice); behavioral testing; in vivo electrophysiology The Journal of neuroscience High 18448641
2003 Loss of both Kv3.1 and Kv3.3 in cerebellar granule cells broadens parallel fiber action potentials and reduces paired-pulse facilitation at parallel fiber–Purkinje cell synapses in a gene dose-dependent manner, due to increased activity-dependent presynaptic Ca2+ influx. Long-term depression was not impaired but was facilitated. Double-knockout mice (Kv3.1/Kv3.3); field potential recordings; paired-pulse facilitation assays; Ca2+ concentration manipulation; LTD induction The Journal of neuroscience High 12930807
2010 Dendritic Kv3.3 channels oppose Ca2+ spike initiation in Purkinje cell distal dendrites. Kv3.3 knockout mice show enhanced dendritic excitability and increased Ca2+ signals specifically in distal dendrites upon climbing fiber activation, demonstrating that Kv3.3 regulates propagation of electrical activity and Ca2+ influx in distal dendrites. Kv3.3 knockout mice; local pharmacology (dendritic K+ channel block); voltage clamp; two-photon Ca2+ imaging throughout dendritic tree Journal of neurophysiology High 20357073
2009 Rescue of motor coordination by Purkinje-cell-targeted Kv3.3 restoration requires intact Kcnc1 (Kv3.1) in deep cerebellar nucleus (DCN) neurons. Loss of Kcnc1 alleles in DCN neurons causes spike broadening and deceleration in DCN neurons and gait ataxia, establishing that fast repolarization in Purkinje cells is important for normal movement velocity while DCN Kv3.1 is required for normal gait patterning. Compound mutant mice (varying Kcnc1/Kcnc3 allele combinations with Purkinje-cell-specific Kv3.3 restoration); in vivo DCN neuron recordings; gait analysis The Journal of neuroscience High 20016089
2010 The R423H mutation (R424H in mouse) in the S4 voltage-sensing domain produces a dominant-negative, non-functional channel subunit distinct from R420H: whereas channels containing R420H and wild-type subunits resemble wild-type channels in gating, channels with R423H and wild-type show hyperpolarized shift in voltage dependence of activation, slower activation, and modestly slower deactivation—properties resembling F448L-containing channels. Xenopus oocyte expression; electrophysiology of heterotetrameric channel mixtures (wild-type + mutant subunits) Human mutation / The Journal of physiology High 19953606 22289912
2014 KCNC3(R420H) has reduced complex glycan adducts compared to wild-type, is retained in the Golgi rather than trafficking to the plasma membrane (only ~24% surface expression by biotinylation), and causes altered Golgi and cellular morphology. Surface biotinylation; immunohistochemistry; electron microscopy; post-translational modification analysis (glycosylation) Neurobiology of disease High 25152487
2017 KCNC3(R423H) expression in mammalian cells results in altered glycosylation and aberrant retention in anterograde and/or endosomal vesicles, with loss of plasma membrane targeting confirmed by absence of current conductance. In Drosophila, co-expression of KCNC3(R423H) with dEGFR rescued eye phenotype, and in mammalian cells KCNC3(R423H) caused aberrant intracellular retention of human EGFR, linking Kv3.3 mutation to disrupted EGFR trafficking. Mammalian cell expression; electrophysiology; Drosophila genetics (eye phenotype rescue); immunofluorescence (EGFR localization); glycosylation analysis PloS one Medium 28467418
2013 Expression of Kv3.3 R424H (mouse equivalent of human R423H) in cerebellar Purkinje cells via lentiviral vectors decreased outward current density, broadened action potentials, elevated basal [Ca2+]i, impaired dendrite development, and caused selective Purkinje cell death. These effects were rescued by blocking P/Q-type Ca2+ channels, linking mutant Kv3.3-induced hyperexcitability to Ca2+-dependent cell death. Lentiviral expression in mouse cerebellar cultures; patch clamp electrophysiology; Ca2+ imaging; P/Q-type Ca2+ channel blocker rescue The Journal of physiology High 24218544
2020 In the lateral superior olive (LSO), Kv3.3 subunits are essential for action potential repolarization; LSO neurons from Kv3.3 KO mice showed approximately doubled AP half-widths, increased Ca2+ influx, increased AP failure rates, and increased AP latency during high-frequency firing. In MNTB neurons, Kv3.1 and Kv3.3 subunits are interchangeable for fast repolarization. Kv3.3 knockout mice; voltage and current clamp in auditory brainstem slices; TEA pharmacology; Ca2+ imaging; high-frequency stimulation protocols The Journal of physiology High 32246836
2022 Kv3.3 (but not Kv3.1) mediates fast repolarization at the calyx of Held presynaptic terminal. Deletion of Kv3.3 reduced presynaptic Kv3 immunolabeling, increased presynaptic AP duration, facilitated excitatory transmitter release with increased vesicle release probability, accelerated activity-dependent vesicle replenishment, and enhanced short-term depression during high-frequency transmission. Kv3.3 KO delayed sound response onset and reduced signal-to-noise ratio. Kv3.3 knockout mice; presynaptic patch clamp at calyx of Held; immunolabeling; in vivo auditory recordings; computational modeling eLife High 35510987
2021 Antisense oligonucleotides (ASOs) against Kcnc3 reduced Kv3.3 mRNA and protein in the cerebellum; in mice homozygous for Kv3.3-G592R, ASO treatment reduced TBK1 activation and Cd63 (multivesicular body marker) levels, restored Hax-1 expression, and rescued rotarod motor behavior, without affecting wild-type mice. Intracerebroventricular ASO infusion; Western blot for TBK1, Hax-1, Cd63; rotarod behavioral assay in wild-type and G592R knock-in mice FASEB journal High 34820911
2018 C-terminal proline deletions (p.Pro583_Pro585del) in Kv3.3 cause slower inactivation and decreased sensitivity to inactivation-accelerating effects of latrunculin B (actin depolymerizer), while membrane trafficking of the channel remains normal. This implicates the C-terminal proline-rich region in the actin-dependent regulation of channel inactivation. Mammalian cell expression; electrophysiology; latrunculin B treatment; membrane trafficking assay Cerebellum Medium 29949095
2020 In zebrafish, an infant-onset Kv3.3 mutation (equivalent to R423H) dramatically and transiently increased Purkinje cell excitability, stunted process extension, impaired dendritic branching and synaptogenesis, and caused rapid Purkinje cell death. Reducing excitability increased early Purkinje cell survival. An adult-onset mutation (equivalent to R420H) did not alter basal tonic firing but reduced excitability during evoked high-frequency spiking, and Purkinje cells matured normally. Zebrafish in vivo electrophysiology; confocal imaging of Purkinje cell morphology; pharmacological reduction of excitability; calcium channel blocker rescue eLife High 32644043
2004 Kv3.3 single-mutant mice showed approximately 100% broader action potentials in Purkinje cells compared to wild-type, and harmaline-induced tremor was virtually absent, establishing an essential role for Kv3.3 in olivocerebellar circuit properties and tremor generation. Kv3.3 protein is immunohistochemically detected in Purkinje cell somata, proximal dendrites, and axonal projections to deep cerebellar nuclei. Kv3.3 single-knockout mice; in vivo harmaline tremor assay; in vitro Purkinje cell electrophysiology; immunohistochemistry The European journal of neuroscience High 15217387
2022 A missense mutation G434V in the voltage sensor of Kcnc3 causes complete loss of voltage-gated conductance and broadening of action potentials in neurons, resulting in decreased neuronal firing and spatial learning deficits in mice. Normal transcription, translation, and trafficking of the channel are unaffected by this mutation. ENU mutagenesis screen; CRISPR knock-in confirmation; electrophysiology of G434V channel; behavioral testing (contextual fear conditioning, spatial memory); trafficking assays PNAS High 35881790
1992 The mouse Kv3.3 (KCNC3) gene is encoded by at least two exons: the N-terminal 212 amino acids are encoded by one exon, and the hydrophobic core (beginning at S1 transmembrane segment) is in a separate exon separated by ~3 kb of intervening sequence. Human KCNC3 maps to chromosome 19. Genomic cloning; cDNA cloning; chromosomal mapping Genomics Medium 1740329
2026 Microtubule-associated protein 6 (MAP6) directly binds the external surface of the Kv3.3 N-terminal T1 tetramer via its 1st and 2nd Mn modules, regulating Kv3.3 axon-dendrite targeting in Purkinje neurons. MAP6 deletion reduces Kv3.3 levels in Purkinje neuron processes. MAP6 knockdown also decreases somatodendritic Cav2.1 levels and reduces Purkinje neuron burst firing. MAP6 knockout mice; shRNA knockdown in Purkinje neurons; direct binding assay (Mn module pulldown with T1 tetramer); immunofluorescence; electrophysiology Neurobiology of disease Medium 42069089
2024 A Kozak sequence variant (c.-6C>A) upstream of KCNC3 increases protein expression without affecting transcription rate, demonstrating that increased translation initiation of KCNC3 transcripts leads to elevated Kv3.3 protein and can cause ataxic disease. Luciferase reporter assays; quantitative PCR; methylation analysis; patient variant identification International journal of molecular sciences Medium 39596509
2016 Kv3.3 downregulation by siRNA in K562 cells increased hemin-induced erythroid differentiation, with decreased activation of p38, CREB, and c-fos signaling molecules, and enhanced cell adhesion through increased integrin β3. siRNA knockdown; flow cytometry; Western blot; cell adhesion assay; fibronectin culture conditions PloS one Low 26849432

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nature genetics 231 16501573
2007 Distribution of Kv3.3 potassium channel subunits in distinct neuronal populations of mouse brain. The Journal of comparative neurology 83 17444489
2010 KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients. Human mutation 72 19953606
2008 Purkinje-cell-restricted restoration of Kv3.3 function restores complex spikes and rescues motor coordination in Kcnc3 mutants. The Journal of neuroscience : the official journal of the Society for Neuroscience 68 18448641
2003 Motor dysfunction and altered synaptic transmission at the parallel fiber-Purkinje cell synapse in mice lacking potassium channels Kv3.1 and Kv3.3. The Journal of neuroscience : the official journal of the Society for Neuroscience 68 12930807
2016 Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating. Cell 61 26997484
2004 Allele-dependent changes of olivocerebellar circuit properties in the absence of the voltage-gated potassium channels Kv3.1 and Kv3.3. The European journal of neuroscience 60 15217387
1992 Genomic organization, nucleotide sequence, and cellular distribution of a Shaw-related potassium channel gene, Kv3.3, and mapping of Kv3.3 and Kv3.4 to human chromosomes 19 and 1. Genomics 47 1740329
2015 Kv3.3 potassium channels and spinocerebellar ataxia. The Journal of physiology 45 26442672
2013 Kv3.3 channels harbouring a mutation of spinocerebellar ataxia type 13 alter excitability and induce cell death in cultured cerebellar Purkinje cells. The Journal of physiology 45 24218544
2008 Kv3.3 channels at the Purkinje cell soma are necessary for generation of the classical complex spike waveform. The Journal of neuroscience : the official journal of the Society for Neuroscience 45 18256249
2011 Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13). PloS one 44 21479265
2003 Inactivation of Kv3.3 potassium channels in heterologous expression systems. The Journal of biological chemistry 44 12923191
2012 Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13. The Journal of physiology 36 22289912
2008 Protein kinase C modulates inactivation of Kv3.3 channels. The Journal of biological chemistry 35 18539595
2009 Rescue of motor coordination by Purkinje cell-targeted restoration of Kv3.3 channels in Kcnc3-null mice requires Kcnc1. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 20016089
2013 Mutation in the kv3.3 voltage-gated potassium channel causing spinocerebellar ataxia 13 disrupts sound-localization mechanisms. PloS one 31 24116147
2001 A prominent soma-dendritic distribution of Kv3.3 K+ channels in electrosensory and cerebellar neurons. The Journal of comparative neurology 30 11745647
2000 Kv3.3 potassium channels in lens epithelium and corneal endothelium. Experimental eye research 30 10712820
2021 Ankyrin-R Links Kv3.3 to the Spectrin Cytoskeleton and Is Required for Purkinje Neuron Survival. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 34785580
2015 Functional analysis helps to define KCNC3 mutational spectrum in Dutch ataxia cases. PloS one 26 25756792
2020 Kv3.1 and Kv3.3 subunits differentially contribute to Kv3 channels and action potential repolarization in principal neurons of the auditory brainstem. The Journal of physiology 25 32246836
2010 Dendritic Kv3.3 potassium channels in cerebellar purkinje cells regulate generation and spatial dynamics of dendritic Ca2+ spikes. Journal of neurophysiology 25 20357073
2005 A C-terminal domain directs Kv3.3 channels to dendrites. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 16354911
2002 Analysis of SCA8 and SCA12 loci in 134 Italian ataxic patients negative for SCA1-3, 6 and 7 CAG expansions. Journal of neurology 24 12140678
2022 Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse. eLife 23 35510987
2021 Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1. Nature communications 22 33741962
2017 A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. PloS one 22 28467418
2014 KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking. Neurobiology of disease 21 25152487
2010 Functional effects of spinocerebellar ataxia type 13 mutations are conserved in zebrafish Kv3.3 channels. BMC neuroscience 20 20712895
2008 Sca13. Cerebellum (London, England) 20 18592334
2006 Immunohistochemical localisation of the voltage gated potassium ion channel subunit Kv3.3 in the rat medulla oblongata and thoracic spinal cord. Brain research 18 16403474
2020 Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo. eLife 15 32644043
2010 Precise localization of the voltage-gated potassium channel subunits Kv3.1b and Kv3.3 revealed in the molecular layer of the rat cerebellar cortex by a pre-embedding immunogold method. Histochemistry and cell biology 14 20857303
2008 Subcellular localization of the voltage-gated potassium channels Kv3.1b and Kv3.3 in the cerebellar dentate nucleus of glutamic acid decarboxylase 67-green fluorescent protein transgenic mice. Neuroscience 14 18682278
2011 Kv3.1b and Kv3.3 channel subunit expression in murine spinal dorsal horn GABAergic interneurones. Journal of chemical neuroanatomy 12 21440618
2005 Spinocerebellar ataxia with mental retardation (SCA13). Cerebellum (London, England) 12 15895558
2017 SCA13 causes dominantly inherited non-progressive myoclonus ataxia. Parkinsonism & related disorders 10 28216058
2010 Kv3.3 immunoreactivity in the vestibular nuclear complex of the rat with focus on the medial vestibular nucleus: targeting of Kv3.3 neurones by terminals positive for vesicular glutamate transporter 1. Brain research 10 20471378
2021 Knockdown of lnc-KCNC3-3:1 Alleviates the Development of Atherosclerosis via Downregulation of JAK1/STAT3 Signaling Pathway. Frontiers in cardiovascular medicine 9 34540913
2021 Suppression of Kv3.3 channels by antisense oligonucleotides reverses biochemical effects and motor impairment in spinocerebellar ataxia type 13 mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 34820911
2018 C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity. Cerebellum (London, England) 8 29949095
2013 Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13). The International journal of neuroscience 7 23215817
2021 Toe Walking as the Initial Symptom of a Spinocerebellar Ataxia 13 in a Patient Presenting with a Mutation in the KCNC3 Gene. Global medical genetics 4 35169784
2016 Voltage-Gated K+ Channel, Kv3.3 Is Involved in Hemin-Induced K562 Differentiation. PloS one 4 26849432
2023 Epilepsy as the symptom of a spinocerebellar ataxia 13 in a patient presenting with a mutation in the KCNC3 gene. BMC neurology 2 37365508
2022 A novel giant non-cholinergic striatal interneuron restricted to the ventrolateral striatum coexpresses Kv3.3 potassium channel, parvalbumin, and the vesicular GABA transporter. Molecular psychiatry 2 33190145
2022 A missense mutation in Kcnc3 causes hippocampal learning deficits in mice. Proceedings of the National Academy of Sciences of the United States of America 2 35881790
2024 Kv3.3 Expression Enhanced by a Novel Variant in the Kozak Sequence of KCNC3. International journal of molecular sciences 1 39596509
2026 Proper localization of the SCA13-linked K+ channel in Purkinje neurons requires a microtubule-stabilizing protein. Neurobiology of disease 0 42069089
2024 A novel KCNC3 gene variant in the voltage-dependent Kv3.3 channel in an atypical form of SCA13 with dominant central vertigo. Frontiers in cellular neuroscience 0 39416683

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