Affinage

KCNK9

Potassium channel subfamily K member 9 · UniProt Q9NPC2

Length
374 aa
Mass
42.3 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 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

KCNK9 (TASK-3/K2P9.1) encodes a two-pore-domain background K+ channel that conducts a time-independent, non-inactivating, pH-sensitive leak current setting resting membrane potential in excitable cells (PMID:10734076, PMID:10747866). The channel is gated extracellularly by protons: His98 in the outer pore acts as the pH sensor (PMID:10734076, PMID:10747866), and cryo-EM at neutral and acidic pH shows that His98 protonation drives C-type inactivation by engaging a cation-π interaction with Trp78, dilating the selectivity-filter mouth while a hydrophobic gate blocks conduction (PMID:38630723); a second, lower cytoplasmic 'X-gate' provides voltage-dependent gating at the inner pore (PMID:19703964, PMID:39637865). TASK-3 functions as a homodimer and assembles heterodimers with TASK-1, TWIK-1, and TASK-5, generating channels with intermediate pH sensitivity, distinct conductance, and altered pharmacology that account for native background currents in motoneurons, cerebellar granule neurons, and carotid body glomus cells (PMID:11733509, PMID:15282272, PMID:30416196, PMID:39215006, PMID:19403596). Surface delivery is tightly controlled: PKA phosphorylation of a C-terminal serine enables 14-3-3 binding that masks a tri-basic COPI retention signal (KRR), while a di-acidic EDE motif drives COPII-dependent ER export and KCC2 interaction supports membrane expression (PMID:12433946, PMID:19139046, PMID:21357689, PMID:17547699, PMID:31269453). Channel activity is modulated by an interface region at the transmembrane/C-terminus boundary that mediates both volatile-anesthetic activation (via Met159) and Gαq/neurotransmitter inhibition (PMID:11886861, PMID:22147752, PMID:25405940), and PKCα phosphorylation of Thr341 reduces current (PMID:17374744). TASK-3 supports oncogenic proliferation and apoptosis resistance in a manner strictly dependent on intact K+ conductance (PMID:12782791), and resides in mitochondria of adrenal zona glomerulosa cells where it controls mitochondrial membrane potential and aldosterone synthesis (PMID:28630209). Loss-of-function mutations in the maternally expressed, paternally imprinted KCNK9 allele—notably G236R, which disrupts the X-gate—cause KCNK9 imprinting (Birk-Barel) syndrome (PMID:18678320, PMID:39637865).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Established that KCNK9 encodes a background K+ channel whose defining property is extracellular pH sensitivity, and pinpointed the molecular sensor.

    Evidence Heterologous expression with patch-clamp and His98 mutagenesis in COS-7, HEK293, and Xenopus oocytes

    PMID:10734076 PMID:10747866

    Open questions at the time
    • Structural basis of how His98 protonation closes the pore not yet resolved
    • Native cellular roles unaddressed
  2. 2001 High

    Showed TASK-3 is not obligately homodimeric but forms functional heterodimers with TASK-1, expanding the diversity of background currents it can generate.

    Evidence Xenopus oocyte co-expression and tandem-linked constructs with voltage clamp, plus immunofluorescence localization

    PMID:11733509

    Open questions at the time
    • Whether heterodimers form in native tissue not yet shown
    • Stoichiometry and assembly determinants undefined
  3. 2002 High

    Mapped the C-terminal/transmembrane interface as the locus for anesthetic activation and neurotransmitter inhibition, and identified a 14-3-3-based trafficking checkpoint controlling surface expression.

    Evidence Site-directed mutagenesis with electrophysiology; yeast two-hybrid, Co-IP, and surface expression assays for 14-3-3

    PMID:11886861 PMID:12433946

    Open questions at the time
    • Identity of the retention signal masked by 14-3-3 not yet defined
    • Kinase generating the 14-3-3 binding site unknown
  4. 2002 Medium

    Linked TASK-3 to a physiological tissue role by showing it dominates the adrenal glomerulosa background conductance and is inhibited by angiotensin II receptor signaling.

    Evidence Northern blot, qRT-PCR, oocyte electrophysiology, and pharmacological matching to native current

    PMID:11875121

    Open questions at the time
    • Native channel identity inferred pharmacologically, not by genetic ablation
    • Downstream consequence for aldosterone not yet tested
  5. 2003 High

    Demonstrated that the oncogenic activity of TASK-3 requires functional K+ conductance, linking channel biophysics directly to tumor biology.

    Evidence Pore mutant (G95E) with dominant-negative validation, proliferation/apoptosis assays, and nude mouse xenograft

    PMID:12782791

    Open questions at the time
    • Signaling pathway connecting K+ flux to proliferation unresolved
    • Tumor types dependent on TASK-3 not delineated
  6. 2003 High

    Resolved the molecular site of ruthenium red block, defining Glu70 in the extracellular loop as a bridging site spanning both subunits.

    Evidence Tandem-construct mutagenesis with Hill analysis and gain-of-function transfer to TASK-1

    PMID:12606773

    Open questions at the time
    • Physiological ligand for the Glu70 site not identified at this stage
  7. 2004 High

    Confirmed TASK-1/TASK-3 heterodimers exist in native neurons and carry physiologically relevant currents, validating heteromerization beyond heterologous systems.

    Evidence Co-IP, dominant-negative suppression, tandem-construct and native motoneuron/granule-neuron patch-clamp with pharmacological profiling

    PMID:14678492 PMID:15282272

    Open questions at the time
    • Relative abundance of homo- vs heteromers in each cell type not quantified
    • Functional consequence of heteromer-specific gating uncharacterized
  8. 2006 High

    Generalized the Glu70 site as a polycation/divalent sensor and identified an activity-dependent transcriptional control of TASK-3 via Ca2+/calcineurin.

    Evidence Charge-swap mutagenesis with single-channel recording; depolarization paradigm with L-type channel/calcineurin blockade and RT-PCR

    PMID:16513667 PMID:16864570

    Open questions at the time
    • Transcription factor downstream of calcineurin not identified
    • In vivo relevance of activity-dependent regulation untested
  9. 2007 High

    Defined the ER-export and PKC regulatory mechanisms: a di-acidic EDE motif drives COPII-dependent export, and PKCα phosphorylation of Thr341 limits Gq-mediated inhibition.

    Evidence Surface expression assays, live imaging, Sar1 dominant-negative; phosphosite mutagenesis, PKCα siRNA, and Gαq antagonist with patch-clamp

    PMID:17374744 PMID:17547699

    Open questions at the time
    • How EDE/COPII export integrates with downstream 14-3-3 checkpoint not unified
    • Whether Gαq acts truly directly on the channel debated at the time
  10. 2008 High

    Established loss-of-function as the disease mechanism for Birk-Barel syndrome and probed pore architecture by disulfide crosslinking the M1P1 loop to the pore.

    Evidence Electrophysiology of the G236R disease variant in homo/heterodimers; cysteine-substitution disulfide trapping between Glu70 and His98

    PMID:18417474 PMID:18678320

    Open questions at the time
    • Imprinting basis of maternal-allele effect not addressed here
    • Structural gating change caused by G236R not yet visualized
  11. 2009 Medium

    Defined dual gating (selectivity filter plus cytoplasmic gate) and refined the 14-3-3 trafficking model by identifying the masked COPI retention signal.

    Evidence Single-channel kinetic modeling with M2/M4/hinge mutagenesis; GST pulldown of COPI with the KRR motif and GFP localization in multiple systems; native carotid body single-channel comparison

    PMID:19139046 PMID:19403596 PMID:19703964

    Open questions at the time
    • Atomic structure of the cytoplasmic gate not yet available
    • Coupling between filter and cytoplasmic gates inferred from kinetics only
  12. 2011 Medium

    Connected the trafficking checkpoint to a defined kinase and resolved the anesthetic activation residue, showing PKA-phosphorylated Ser373 enables 14-3-3-mediated export and Met159 forms the anesthetic site.

    Evidence In vitro kinase assay with surface GFP assay; M159C NEM modification with tandem dimers and electrophysiology

    PMID:21357689 PMID:22147752

    Open questions at the time
    • In vivo kinase regulation of trafficking not tested
    • Anesthetic binding pocket not structurally resolved at this point
  13. 2013 High

    Localized TASK-3 to mitochondria of aldosterone-producing cells and tied it functionally to steroidogenesis, while refining the disease mutant as hypomorphic rather than null.

    Evidence Yeast two-hybrid, immunoprecipitation, EM, and TASK-3 knockout mouse mitochondrial/aldosterone phenotyping; electrophysiology of G236R with pharmacological rescue

    PMID:24342771 PMID:28630209

    Open questions at the time
    • Mechanism by which a K+ channel sets mitochondrial membrane potential unclear
    • How residual G236R current relates to clinical severity unresolved
  14. 2014 High

    Defined in vivo neuronal roles: TASK-3 sets cold-sensing thresholds in TRPM8 neurons and is the target of neurotensin-NTS1/Gαq signaling in dentate gyrus granule cells.

    Evidence TASK-3 knockout behavioral assays with FACS profiling of TRPM8 neurons; brain-slice patch-clamp with Co-IP showing NTS1-induced Gαq/TASK-3 association

    PMID:25199828 PMID:25405940

    Open questions at the time
    • Whether Gαq contacts the channel directly versus through an adaptor not fully settled
    • Contribution of heteromers to these phenotypes not dissected
  15. 2015 Medium

    Localized the binding site of breathing-stimulant inhibitors to the intracellular pore, identifying L122 and G236 as drug-contact residues.

    Evidence Homology modeling, docking, and mutagenesis with Ussing chamber electrophysiology for PKTHPP, A1899, and doxapram

    PMID:26268529

    Open questions at the time
    • Site inferred from modeling/mutagenesis without a co-structure
    • Selectivity over TASK-1 not addressed
  16. 2018 Medium

    Identified TWIK-1 as a further heterodimeric partner of TASK-3 shaping dentate gyrus granule cell excitability.

    Evidence Co-IP from hippocampus and COS-7 cells, shRNA knockdown, and patch-clamp of granule cells

    PMID:30416196

    Open questions at the time
    • Stoichiometry and gating of TWIK-1/TASK-3 heteromer not fully defined
    • Single-lab Co-IP without structural confirmation
  17. 2019 Medium

    Added KCC2 as a trafficking partner required for TASK-3 surface expression and characterized species- and pore-dependent doxapram pharmacology.

    Evidence Co-IP, KCC2 shRNA, fractionation, chemogenetic rescue, and patch-clamp; enantiomer and pore-residue mutagenesis with human/mouse comparison

    PMID:31269453 PMID:31423744

    Open questions at the time
    • Whether KCC2 acts via direct interaction or chaperone effect not fully resolved
    • Structural basis of doxapram species selectivity unknown
  18. 2020 Medium

    Showed that the natural compound withaferin A inhibits TASK-3 at defined pore residues and that its cytotoxicity in cancer cells is TASK-3-dependent, reinforcing the oncogenic relevance of the channel.

    Evidence Patch-clamp, docking, F125/L197 mutagenesis, and TASK-3 overexpression/knockdown viability assays in MDA-MB-231 cells

    PMID:32563149

    Open questions at the time
    • Binding pose inferred from docking, not co-structure
    • In vivo antitumor efficacy untested
  19. 2022 Medium

    Broadened the disease genotype-phenotype map, showing KCNK9 imprinting syndrome arises from both gain and loss of conductance with altered regulatory control as the common theme.

    Evidence Electrophysiology of 15 variants with 3D molecular dynamics modeling and clinical/facial phenotyping

    PMID:35698242

    Open questions at the time
    • Structural validation relied on modeling rather than experimental structures
    • Mechanistic link between altered regulation and phenotype not established
  20. 2024 High

    Provided the structural mechanism of pH gating and disease, resolving cryo-EM structures that show His98-Trp78 cation-π-driven C-type inactivation and an X-gate disrupted by the G236R variant.

    Evidence Cryo-EM of TASK-3 at two pH states and of TASK-1/TASK-3 G236R, with MD simulations, mutagenesis, and electrophysiology; plus TASK-5/TASK-3 heterodimer characterization

    PMID:38630723 PMID:39215006 PMID:39637865

    Open questions at the time
    • Structures of regulatory complexes (14-3-3, KCC2, Gαq) with the channel not yet determined
    • Mitochondrial channel structure/function relationship unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many regulatory inputs (PKA/14-3-3 trafficking, PKCα, Gαq, KCC2, heteromerization) are integrated at the channel in vivo, and how K+ conductance is mechanistically coupled to oncogenesis and mitochondrial/aldosterone control, remains unresolved.
  • No structure of TASK-3 bound to a trafficking or signaling partner
  • Causal link between channel flux and proliferation undefined
  • Mechanism by which a plasma-membrane-type K+ channel operates in mitochondria unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140299 molecular sensor activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 3 GO:0005739 mitochondrion 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-9609507 Protein localization 5 R-HSA-112316 Neuronal System 4 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
COPB1GNAQKCNK1KCNK15KCNK3PRKCASLC12A5YWHAZ
Complex memberships
TASK-1/TASK-3 heterodimerTASK-5/TASK-3 heterodimerTWIK-1/TASK-3 heterodimer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TASK-3 (KCNK9) encodes a time-independent, non-inactivating K+-selective background current. Mutation of histidine at position 98 to aspartate abolished extracellular pH sensitivity, identifying His98 as the critical pH sensor. Heterologous expression in COS-7 cells, whole-cell and single-channel patch-clamp, site-directed mutagenesis The Journal of biological chemistry High 10734076 10747866
2000 His98, located at the outer pore adjacent to the selectivity filter, is an essential component of the extracellular pH sensor; substitution of His98 with asparagine or tyrosine abolished pH sensitivity. Single-channel recordings in HEK293 cells showed inwardly rectifying I-V relationship with open probability increasing markedly with depolarization. Xenopus oocyte expression, HEK293 cell-attached patch-clamp, site-directed mutagenesis The Journal of biological chemistry High 10747866
2001 TASK-1 and TASK-3 form functional heterodimers when co-expressed in Xenopus oocytes. A tandem-linked TASK-3/TASK-1 construct yielded currents with intermediate pH sensitivity and ruthenium red insensitivity (TASK-1-like). Epitope-tagged channels localized primarily to the plasma membrane in mammalian cells. Xenopus oocyte co-expression, tandem-linked constructs, two-electrode voltage clamp, immunofluorescence localization in mammalian cells The Journal of biological chemistry High 11733509
2002 A six-residue sequence at the beginning of the cytoplasmic C-terminus (interface of final transmembrane domain and C-terminus) is required for both volatile anesthetic (halothane) activation and neurotransmitter (TRH) inhibition of TASK-3; mutations in this region virtually abolished both effects. The identified phosphorylation site within this region was not required for modulation. Site-directed mutagenesis, heterologous expression, whole-cell electrophysiology The Journal of biological chemistry High 11886861
2002 TASK-3 C-terminal domain interacts with 14-3-3 adapter proteins via a C-terminal RRx(S/T)x motif. This interaction promotes surface membrane expression; deletion of a single C-terminal amino acid abolished 14-3-3 binding and strongly reduced macroscopic currents. Co-injection of 14-3-3ζ increased TASK-3 current by ~70% in oocytes. TASK-1 and 14-3-3 co-immunoprecipitated from synaptic membranes. Yeast two-hybrid, co-immunoprecipitation, Xenopus oocyte voltage clamp, GFP surface expression assay in HEK293 cells, truncation/point mutagenesis The Journal of physiology High 12433946
2002 TASK-3 dominates the background K+ conductance of rat adrenal glomerulosa cells. The pharmacological profile of native glomerulosa current (ruthenium red sensitivity in micromolar range, weak acid sensitivity) matches TASK-3, and TASK-3 current is inhibited by AT1a angiotensin II receptor stimulation when co-expressed. Northern blot, quantitative RT-PCR, Xenopus oocyte electrophysiology, pharmacological characterization Molecular endocrinology Medium 11875121
2003 Oncogenic functions of TASK3 (KCNK9) — promoting proliferation in low serum, resistance to apoptosis, and tumor growth in nude mice — require intact K+ channel function. A pore mutation (G95E) abolished both K+ current and oncogenic activity. G95E acts as a dominant-negative, suppressing wild-type TASK3 current and tumorigenicity when co-expressed. Site-directed mutagenesis, patch-clamp electrophysiology, cell proliferation assays, apoptosis assays, nude mouse xenograft Proceedings of the National Academy of Sciences of the United States of America High 12782791
2003 Ruthenium red inhibits TASK-3 by simultaneously binding glutamate 70 (Glu70) on both subunits of the dimer. Mutation of Glu70 to Arg or Cys in either subunit of a tandem construct abolished RR inhibition. The Hill coefficient of ~1.0 indicates one RR molecule bridges both subunits. Introducing Glu at position 70 of TASK-1 (K70E) conferred RR sensitivity. Site-directed mutagenesis of tandem constructs, Xenopus oocyte electrophysiology, pharmacological dose-response analysis Molecular pharmacology High 12606773
2004 TASK-1/TASK-3 heterodimers are expressed in native hypoglossal motoneurons. Co-immunoprecipitation from transfected mammalian cell membranes confirmed physical association. A dominant-negative TASK-1(Y191F) suppressed TASK-3 currents. Heteromeric channels display intermediate pH sensitivity (pK ~7.3) and are activated (not inhibited) by high isoflurane, matching native motoneuron TASK currents. Co-immunoprecipitation, dominant-negative suppression, tandem-linked heterodimer electrophysiology, native neuron patch-clamp, pharmacological profiling The Journal of neuroscience High 15282272
2004 Native 38-pS K+ channels in cerebellar granule neurons include both homomeric TASK-3 and heteromeric TASK-1/TASK-3 channels, identified by differential sensitivity to ruthenium red and extracellular pH changes matching cloned homomers and heterodimers. Single-channel patch-clamp of cultured cerebellar granule neurons and COS-7-expressed cloned channels, pharmacological profiling with ruthenium red and pH The Journal of physiology Medium 14678492
2006 Glutamate 70 (Glu70) in the extracellular loop of TASK-3 mediates sensitivity to divalent cations (Ca2+, Mg2+) and polycations (spermine, ruthenium red). Replacing Glu70 with Lys or Arg abolished divalent cation sensitivity; the reverse mutation in TASK-1 (K70E) induced this sensitivity. Spermine and ruthenium red also decrease open probability likely by binding Glu70. Site-directed mutagenesis, HEK293 cell single-channel and whole-cell electrophysiology, charge-swap experiments The Journal of physiology High 16513667
2006 Transcription of TASK-3 in cerebellar granule neurons is regulated by membrane depolarization through Ca2+ entry via L-type channels and the downstream effector calcineurin. Blocking L-type Ca2+ channels or calcineurin abrogated TASK-3 mRNA and protein upregulation and the IKso conductance, causing hyperexcitability. In vitro neuronal culture in depolarizing/non-depolarizing KCl conditions, pharmacological blockade of L-type channels and calcineurin, RT-PCR, patch-clamp The Journal of biological chemistry Medium 16864570
2007 Di-acidic motif EDE in the proximal C-terminus of TASK-3 is required for efficient ER export and surface membrane expression. Mutation of the two glutamate residues (ADA mutant) markedly reduced surface expression and retained the channel in the ER. ER export of TASK-3 requires COPII machinery (blocked by dominant-negative Sar1H79G). Luminometric surface expression assay, Xenopus oocyte voltage clamp, live-cell GFP imaging in COS-7 cells, Sar1 dominant-negative co-expression, chimeric constructs Traffic High 17547699
2007 Protein kinase C (PKCα) phosphorylates Thr341 in the C-terminus of human TASK3, thereby reducing channel current. Gαq-coupled M3 muscarinic receptor inhibition of TASK3 occurs through a direct action of Gαq on the channel (not through PKC), while PKC activation opposes and limits the duration of Gq-mediated inhibition. Site-directed mutagenesis of phosphorylation site, siRNA knockdown of PKCα, selective PKC inhibitors, Gαq antagonist (YM-254890), whole-cell patch-clamp Molecular pharmacology High 17374744
2008 The Birk Barel syndrome missense mutation G236R in the maternal copy of KCNK9 fully abolishes channel currents both when functioning as a homodimer and as a heterodimer with K2P3.1 (TASK-1), establishing loss-of-function as the disease mechanism. Electrophysiological characterization of mutant channels in heterologous expression system, genetic mapping American journal of human genetics High 18678320
2008 The M1P1 extracellular loop of TASK-3 lies close to the pore and regulates channel activity. Disulfide bond formation between Cys substitutions at Glu70 (M1P1 loop) and His98 (pore) in tandem constructs confirms their spatial proximity. The M1P1 loop also participates in pH regulation of TASK-3. Site-directed mutagenesis with cysteine substitutions, tandem-fixed constructs, dithiothreitol/cadmium probing, loop-swap chimeras, patch-clamp The Journal of biological chemistry High 18417474
2009 TASK-3 surface expression is controlled by 14-3-3 binding masking a tri-basic COPI retention signal (KRR) in the C-terminus. When 14-3-3 binding is disabled, KRR is exposed and binds COPI coatomer, retaining the channel in the Golgi. TASK-3 also has an independent di-basic N-terminal retention signal (KR). 14-3-3 binding does not affect dimeric assembly. Mutational analysis in Xenopus oocytes, mammalian cells and yeast; GST pulldown of COPI with KRR motif; GFP-tagged channel localization; dominant-negative suppression of dimerization The Journal of physiology High 19139046
2009 TASK-1/TASK-3 heteromers are the major oxygen-sensitive background K+ channels in rat carotid body glomus cells, contributing ~75% of TASK-like current. Discrimination among TASK-1, TASK-3, and TASK-1/3 heteromers was achieved by comparing single-channel conductances in defined Mg2+ conditions and ruthenium red sensitivity in native cells vs. cloned channels. Single-channel patch-clamp of native carotid body cells and cloned channels in outside-out/cell-attached configuration, pharmacological profiling with ruthenium red and methanandamide The Journal of physiology Medium 19403596
2009 TASK-3 voltage-dependent gating involves a cytoplasmic gate in addition to the selectivity filter. Mutations in M2 (N133A) and M4 (A237T) increase open probability and shift voltage dependence, while mutating conserved hinge glycines (G117A, G231A) decreases open probability. Two routes out of the open state indicate dual gating at selectivity filter and cytoplasmic mouth. Two-electrode voltage clamp, single-channel recording, kinetic modeling, site-directed mutagenesis The Journal of physiology Medium 19703964
2011 Protein kinase A (PKA/cAMP-dependent protein kinase) phosphorylates Ser373 in the C-terminus of TASK-3 (K2P9.1), and this phosphorylation enables 14-3-3 binding to overcome ER retention by βCOP, thus promoting forward trafficking to the plasma membrane. In vitro phosphorylation assays, bioinformatics candidate selection, electrophysiology in HEK293 cells, cell surface GFP assay The Journal of biological chemistry Medium 21357689
2011 Met159 in TASK-3 is essential for volatile anesthetic activation and contributes to the anesthetic binding site. Covalent modification of M159C by NEM irreversibly activated the channel and rendered it resistant to inhibition by both acidic pH and active Gαq protein. A single modified subunit in a wild-type/M159C tandem is sufficient for activation, indicating cross-talk between subunits. Site-directed mutagenesis (M159C, M159W, M159F), cysteine-reactive NEM modification, tandem dimers, electrophysiology in Fischer rat thyroid cells (Ussing chamber) Molecular pharmacology High 22147752
2012 N-linked glycosylation of TASK-3 (K2P9.1) occurs at the conserved consensus site; however, disruption of glycosylation causes only a small reduction in cell surface channels with no detectable functional change in K+ current, in contrast to TASK-1 where glycosylation loss significantly reduces surface expression and current. Flow cytometry surface expression assay, patch-clamp, site-directed mutagenesis of glycosylation site, tunicamycin treatment The Journal of biological chemistry Medium 23250752
2013 The Birk Barel G236R mutant TASK-3 produces a small, inwardly rectifying current (not zero current) with altered responses to extracellular acidification, zinc, and Gαq-coupled muscarinic receptors compared to wild-type. A gain-of-function second mutation A237T and the NSAID flufenamic acid partially restore outward current through G236R channels. Whole-cell electrophysiology of wild-type and G236R mutant TASK-3, pharmacological profiling, double mutants Molecular pharmacology Medium 24342771
2013 TASK-3 channels are present in mitochondria of aldosterone-producing zona glomerulosa cells, confirmed by yeast two-hybrid, immunoprecipitation, and electron microscopy. Genetic deletion of TASK-3 from mice disrupts mitochondrial morphology, mitochondrial membrane potential, and aldosterone production without changing plasma membrane potential of glomerulosa cells. Yeast two-hybrid, immunoprecipitation, electron microscopy, mitochondrial membrane potential measurements, aldosterone assays in TASK-3 knockout mice Hypertension High 28630209
2014 TASK-3 channels are highly enriched in a subpopulation of TRPM8-positive cold-sensitive neurons. Blockade or genetic knockout of TASK-3 reduces the thermal threshold of cold neurons and causes hypersensitivity to cold in mice, establishing TASK-3 as a modulator of thermosensation in peripheral cold receptors. BAC transgenesis, FACS purification of TRPM8 neurons, molecular profiling, pharmacological blockade, TASK-3 knockout mouse behavioral assays Cell reports High 25199828
2014 Neurotensin (NT) excites dentate gyrus granule cells via NTS1 receptor-mediated inhibition of TASK-3 K+ channels through direct coupling of Gαq/11 to TASK-3 (not via PLC, IP3-Ca2+, or PKC). Co-immunoprecipitation showed NTS1 activation induced physical association of Gαq/11 with TASK-3. Whole-cell patch-clamp in brain slices, pharmacological dissection, co-immunoprecipitation, receptor-specific antagonists Cerebral cortex Medium 25405940
2015 Breathing stimulants PKTHPP, A1899, and doxapram inhibit TASK-3 by binding within the intracellular pore region. Mutagenesis identified residues L122 and G236 as critical for drug binding; L122D and G236D mutations increased IC50 >1000-fold. These same mutations conferred resistance to all three compounds. Homology modeling, molecular docking, site-directed mutagenesis, Ussing chamber electrophysiology in Fischer rat thyroid monolayers Molecular pharmacology Medium 26268529
2018 TWIK-1 physically associates with TASK-3 in dentate gyrus granule cells (DGGCs) and in COS-7 cells. TWIK-1/TASK-3 heterodimeric channels display outwardly rectifying currents and contribute to intrinsic excitability of DGGCs. Neurotensin-NTS1 signaling depolarizes DGGCs by inhibiting TWIK-1/TASK-3 heterodimeric channels. Co-immunoprecipitation from mouse hippocampus and COS-7 cells, shRNA knockdown of each subunit, patch-clamp of DGGCs Experimental & molecular medicine Medium 30416196
2019 KCC2 interacts with TASK-3 (KCNK9) channels and is required for their membrane expression. KCC2 knockdown in rat dentate gyrus neurons reduces TASK-3 surface expression, decreases leak K+ currents, and depolarizes resting membrane potential, leading to increased neuronal excitability and altered network rhythmogenesis. Co-immunoprecipitation of KCC2 and TASK-3, shRNA knockdown of KCC2, patch-clamp, subcellular fractionation, chemogenetic rescue Cell reports High 31269453
2019 Doxapram inhibits human TASK-3 (hKCNK9) and TASK-1 channels with equal potency (unlike mouse channels where it is TASK-1-selective). Inhibition is attenuated by C-terminus truncation or mutations of hydrophobic pore-lining residues, while an extracellular zinc binding site is not affected. The (+)-enantiomer GAL-054 is more potent than doxapram; the (−)-enantiomer GAL-053 has little effect. Whole-cell patch-clamp in tsA201 cells, site-directed mutagenesis of pore residues, chirally separated enantiomers, species comparison (human vs. mouse) Acta physiologica Medium 31423744
2020 Withaferin A (WFA) inhibits TASK-3 channels in a dose-dependent, voltage-independent manner. Molecular docking and mutagenesis identified F125 and L197 as critical residues for WFA binding; F125A, L197V, and double mutant markedly reduced WFA inhibition. The cytotoxic effect of WFA in MDA-MB-231 cells depends on TASK-3 expression. Patch-clamp in HEK-293 cells, molecular docking, site-directed mutagenesis, TASK-3 overexpression and shRNA knockdown in cancer cells, cell viability assays Biomedicine & pharmacotherapy Medium 32563149
2022 KCNK9 imprinting syndrome variants cause both gain and loss of TASK-3 channel conductance, but the most consistent functional impact is altered channel regulation (loss of regulatory control). An additional mutational hotspot was identified at p.Arg131. 3D protein modeling and in vitro electrophysiology define the structural basis of variant effects. In vitro electrophysiology of 15 novel KCNK9 variants, computational 3D molecular mechanics and dynamics, clinical genetics, facial phenotyping Genome medicine Medium 35698242
2024 Cryo-EM structures of human TASK-3 at neutral and acidic pH revealed that extracellular acidification drives C-type inactivation through selectivity filter rearrangement: the SF mouth dilates while a hydrophobic gate blocks the pore. His98 protonation shifts the equilibrium toward the inactivated state by engaging a cation-π interaction with Trp78, as confirmed by MD simulations and mutagenesis. Cryo-EM structural determination at two pH values, molecular dynamics simulations, site-directed mutagenesis of His98 and Trp78, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 38630723
2024 Cryo-EM structures of human TASK-1 and TASK-3 (including the G236R KIS variant) reveal a conserved lower X-gate gating mechanism. The G236R substitution disrupts the X-gate, providing structural explanation for loss-of-function in KCNK9 imprinting syndrome. Combined functional studies confirmed X-gate conformational changes underlie pH-dependent inhibition. Cryo-EM structure determination of wild-type TASK-1, TASK-3, and G236R variant; functional electrophysiology Structure High 39637865
2024 TASK-5 (KCNK15) forms functional heterodimers with TASK-3 at the plasma membrane. TASK-5/TASK-3 heteromers show altered single-channel conductance, modified Gq-coupled receptor inhibition, and distinct pharmacological sensitivity compared to TASK-3 homodimers. TASK-5 reduces surface expression of TASK channels when forming heteromers. Co-expression in heterologous cells, single-channel electrophysiology, pharmacological profiling, surface expression assays Nature communications Medium 39215006

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 TASK-3, a new member of the tandem pore K(+) channel family. The Journal of biological chemistry 313 10734076
2000 TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. The Journal of biological chemistry 271 10747866
2003 Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer cell 208 12676587
2001 Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits. The Journal of biological chemistry 207 11733509
2004 Motoneurons express heteromeric TWIK-related acid-sensitive K+ (TASK) channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 15282272
2002 Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action. The Journal of biological chemistry 170 11886861
2008 Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. American journal of human genetics 143 18678320
2003 Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function. Proceedings of the National Academy of Sciences of the United States of America 143 12782791
2003 Contribution of TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 channels to the control of activity modes in thalamocortical neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 143 12878686
2009 Heteromeric TASK-1/TASK-3 is the major oxygen-sensitive background K+ channel in rat carotid body glomus cells. The Journal of physiology 128 19403596
2002 Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3. The Journal of physiology 116 12433946
2001 Expression pattern in brain of TASK-1, TASK-3, and a tandem pore domain K(+) channel subunit, TASK-5, associated with the central auditory nervous system. Molecular and cellular neurosciences 115 11749039
2004 Functional expression of TASK-1/TASK-3 heteromers in cerebellar granule cells. The Journal of physiology 108 14678492
2006 Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. Journal of neurophysiology 95 16760342
2002 TASK-3 dominates the background potassium conductance in rat adrenal glomerulosa cells. Molecular endocrinology (Baltimore, Md.) 93 11875121
2008 TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions. The Journal of biological chemistry 90 18375952
2007 TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. The Journal of pharmacology and experimental therapeutics 85 17875609
2001 Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel. Neuropharmacology 84 11249964
2003 Ruthenium red inhibits TASK-3 potassium channel by interconnecting glutamate 70 of the two subunits. Molecular pharmacology 77 12606773
2014 Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell reports 72 25199828
2004 Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc. The Journal of physiology 69 15284350
2007 Mitochondrial expression of the two-pore domain TASK-3 channels in malignantly transformed and non-malignant human cells. Virchows Archiv : an international journal of pathology 68 18094996
2018 TWIK-1/TASK-3 heterodimeric channels contribute to the neurotensin-mediated excitation of hippocampal dentate gyrus granule cells. Experimental & molecular medicine 65 30416196
2009 Intracellular traffic of the K+ channels TASK-1 and TASK-3: role of N- and C-terminal sorting signals and interaction with 14-3-3 proteins. The Journal of physiology 64 19139046
2016 A monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis. Nature communications 63 26842342
2006 Effects of divalent cations and spermine on the K+ channel TASK-3 and on the outward current in thalamic neurons. The Journal of physiology 59 16513667
2012 Task3 potassium channel gene invalidation causes low renin and salt-sensitive arterial hypertension. Endocrinology 56 22878402
2004 Altered expression of KCNK9 in colorectal cancers. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 56 15601307
2009 Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons. The European journal of neuroscience 54 19508695
2007 G(alpha)q-mediated regulation of TASK3 two-pore domain potassium channels: the role of protein kinase C. Molecular pharmacology 54 17374744
2014 Targeting two-pore domain K(+) channels TREK-1 and TASK-3 for the treatment of depression: a new therapeutic concept. British journal of pharmacology 53 25263033
2007 Sequence-based bioinformatic prediction and QUASEP identify genomic imprinting of the KCNK9 potassium channel gene in mouse and human. Human molecular genetics 53 17704508
2011 Discovery of a pharmacologically active antagonist of the two-pore-domain potassium channel K2P9.1 (TASK-3). ChemMedChem 52 21916012
2019 KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels. Cell reports 50 31269453
2014 Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index. PLoS genetics 50 25078964
2007 A di-acidic sequence motif enhances the surface expression of the potassium channel TASK-3. Traffic (Copenhagen, Denmark) 49 17547699
2002 TASK-1, TASK-2, TASK-3 and TRAAK immunoreactivities in the rat carotid body. Brain research 49 12231257
2017 Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty. Hormone research in paediatrics 47 28672280
2010 TASK1 and TASK3 potassium channels: determinants of aldosterone secretion and adrenocortical zonation. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 42 20049674
2007 Identification of a region in the TASK3 two pore domain potassium channel that is critical for its blockade by methanandamide. British journal of pharmacology 38 17828294
2015 TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes. Journal of molecular and cellular cardiology 36 25655935
2011 Reduction of breast cancer cell migration via up-regulation of TASK-3 two-pore domain K+ channel. Acta physiologica (Oxford, England) 36 21910834
2006 Melanoma cells exhibit strong intracellular TASK-3-specific immunopositivity in both tissue sections and cell culture. Cellular and molecular life sciences : CMLS 36 17013562
2013 Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Molecular pharmacology 34 24342771
2013 Severe hyperaldosteronism in neonatal Task3 potassium channel knockout mice is associated with activation of the intraadrenal renin-angiotensin system. Endocrinology 33 23698720
2014 Silencing the KCNK9 potassium channel (TASK-3) gene disturbs mitochondrial function, causes mitochondrial depolarization, and induces apoptosis of human melanoma cells. Archives of dermatological research 32 25318378
2011 Inhibition of TASK-3 (KCNK9) channel biosynthesis changes cell morphology and decreases both DNA content and mitochondrial function of melanoma cells maintained in cell culture. Melanoma research 32 21512417
2008 The two-pore domain potassium channel TASK3 functionally impacts glioma cell death. Journal of neuro-oncology 32 18217213
2008 The M1P1 loop of TASK3 K2P channels apposes the selectivity filter and influences channel function. The Journal of biological chemistry 32 18417474
2020 Withaferin A suppresses breast cancer cell proliferation by inhibition of the two-pore domain potassium (K2P9) channel TASK-3. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 32563149
2016 KCNK9 imprinting syndrome-further delineation of a possible treatable disorder. American journal of medical genetics. Part A 31 27151206
2006 Membrane potential-regulated transcription of the resting K+ conductance TASK-3 via the calcineurin pathway. The Journal of biological chemistry 30 16864570
2004 Differential distribution of TASK-1, TASK-2 and TASK-3 immunoreactivities in the rat and human cerebellum. Cellular and molecular life sciences : CMLS 30 15197476
2008 Both TASK-3 and TREK-1 two-pore loop K channels are expressed in H295R cells and modulate their membrane potential and aldosterone secretion. American journal of physiology. Endocrinology and metabolism 28 18854423
2015 Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore. Molecular pharmacology 27 26268529
2005 Protective effects of TASK-3 (KCNK9) and related 2P K channels during cellular stress. Brain research 27 15649441
2005 A TASK3 channel (KCNK9) mutation in a genetic model of absence epilepsy. Journal of molecular neuroscience : MN 27 15781965
2017 Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3. Biochemical and biophysical research communications 25 28882594
2009 The response of the tandem pore potassium channel TASK-3 (K(2P)9.1) to voltage: gating at the cytoplasmic mouth. The Journal of physiology 25 19703964
2005 TASK-3 immunoreactivity shows differential distribution in the human gastrointestinal tract. Virchows Archiv : an international journal of pathology 25 15789217
2017 Functional TASK-3-Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells. Hypertension (Dallas, Tex. : 1979) 24 28630209
2019 TASK-3 Gene Knockdown Dampens Invasion and Migration and Promotes Apoptosis in KATO III and MKN-45 Human Gastric Adenocarcinoma Cell Lines. International journal of molecular sciences 22 31810225
2018 TASK-3 Downregulation Triggers Cellular Senescence and Growth Inhibition in Breast Cancer Cell Lines. International journal of molecular sciences 22 29596383
2002 Tandem pore domain K(+)-channel TASK-3 (KCNK9) and idiopathic absence epilepsies. American journal of medical genetics 22 11857586
2012 N-glycosylation-dependent control of functional expression of background potassium channels K2P3.1 and K2P9.1. The Journal of biological chemistry 21 23250752
2011 Covalent modification of a volatile anesthetic regulatory site activates TASK-3 (KCNK9) tandem-pore potassium channels. Molecular pharmacology 21 22147752
2008 Excitability of pontine startle processing neurones is regulated by the two-pore-domain K+ channel TASK-3 coupled to 5-HT2C receptors. The European journal of neuroscience 21 18691333
2006 Striatal cholinergic interneurons express a receptor-insensitive homomeric TASK-3-like background K+ current. Journal of neurophysiology 21 17167057
2011 Protein kinase A is central for forward transport of two-pore domain potassium channels K2P3.1 and K2P9.1. The Journal of biological chemistry 20 21357689
2020 Synthesis and cellular effects of a mitochondria-targeted inhibitor of the two-pore potassium channel TASK-3. Pharmacological research 19 33338625
2019 Effects of the ventilatory stimulant, doxapram on human TASK-3 (KCNK9, K2P9.1) channels and TASK-1 (KCNK3, K2P3.1) channels. Acta physiologica (Oxford, England) 19 31423744
2012 Modulation of K2P3.1 (TASK-1), K2P9.1 (TASK-3), and TASK-1/3 heteromer by reactive oxygen species. Pflugers Archiv : European journal of physiology 18 23007462
2018 Selective Knockdown of TASK3 Potassium Channel in Monoamine Neurons: a New Therapeutic Approach for Depression. Molecular neurobiology 17 30088175
2015 The role of protein-protein interactions in the intracellular traffic of the potassium channels TASK-1 and TASK-3. Pflugers Archiv : European journal of physiology 17 25559843
2014 Screening individuals with intellectual disability, autism and Tourette's syndrome for KCNK9 mutations and aberrant DNA methylation within the 8q24 imprinted cluster. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 17 24980697
2021 TASK1 and TASK3 in orexin neuron of lateral hypothalamus contribute to respiratory chemoreflex by projecting to nucleus tractus solitarius. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 33817828
2020 TASK-1 and TASK-3 channels modulate pressure overload-induced cardiac remodeling and dysfunction. American journal of physiology. Heart and circulatory physiology 15 31977249
2019 Novel variant in the KCNK9 gene in a girl with Birk Barel syndrome. European journal of medical genetics 14 30690205
2008 Altered neuronal expression of TASK1 and TASK3 potassium channels in rodent and human autoimmune CNS inflammation. Neuroscience letters 14 18824070
2022 Tandem pore domain acid-sensitive K channel 3 (TASK-3) regulates visual sensitivity in healthy and aging retina. Science advances 13 36070380
2022 Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. Genome medicine 12 35698242
2019 Structure/Activity Analysis of TASK-3 Channel Antagonists Based on a 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine. International journal of molecular sciences 12 31067753
2024 C-type inactivation and proton modulation mechanisms of the TASK3 channel. Proceedings of the National Academy of Sciences of the United States of America 11 38630723
2024 Potassium channel TASK-5 forms functional heterodimers with TASK-1 and TASK-3 to break its silence. Nature communications 10 39215006
2019 Spinal TASK-1 and TASK-3 modulate inflammatory and neuropathic pain. European journal of pharmacology 10 31472119
2014 Immunocytochemical localization of TASK-3 protein (K2P9.1) in the rat brain. Cellular and molecular neurobiology 10 24077856
2014 Neurotensinergic Excitation of Dentate Gyrus Granule Cells via Gαq-Coupled Inhibition of TASK-3 Channels. Cerebral cortex (New York, N.Y. : 1991) 10 25405940
2004 Immunolocalization of TASK-3 (KCNK9) to a subset of cortical neurons in the rat CNS. Biochemical and biophysical research communications 10 15178438
2003 Heterogeneous expression of TASK-3 and TRAAK in rat paraganglionic cells. Histochemistry and cell biology 10 14574589
2018 The Insensitivity of TASK-3 K₂P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure. International journal of molecular sciences 9 30126179
2013 Enhancement of TWIK-related acid-sensitive potassium channel 3 (TASK3) two-pore domain potassium channel activity by tumor necrosis factor α. The Journal of biological chemistry 9 24307172
2024 Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease. Structure (London, England : 1993) 8 39637865
2023 Allelic chromatin structure precedes imprinted expression of Kcnk9 during neurogenesis. Genes & development 7 37821107
2022 Epigenomic Analysis Reveals the KCNK9 Potassium Channel as a Potential Therapeutic Target for Adenomyosis. International journal of molecular sciences 7 35682653
2021 Expression of Proton-Sensitive GPR31, GPR151, TASK1 and TASK3 in Common Skin Tumors. Cells 7 35011589
2019 Changes in the expression of the potassium channels TASK1, TASK3 and TRESK in a rat model of oral squamous cell carcinoma and their relation to malignancy. Archives of oral biology 7 30818127
2006 The background K(+) channel TASK-3 is regulated at both the transcriptional and post-transcriptional levels. Biochemical and biophysical research communications 7 16925981
2023 KCNK9 mediates the inhibitory effects of genistein on hepatic metastasis from colon cancer. Clinics (Sao Paulo, Brazil) 6 36905879
2021 Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer. Cancers 6 34885139
2010 Immunocytochemical localization of TASK-3 (K(2P)9.1) channels in monoaminergic and cholinergic neurons. Cellular and molecular neurobiology 6 21082237

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