Affinage

KCNK9

Potassium channel subfamily K member 9 · UniProt Q9NPC2

Length
374 aa
Mass
42.3 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNK9 (TASK-3/K2P9.1) encodes a two-pore-domain background potassium leak channel that sets resting membrane potential in neurons, adrenal glomerulosa cells, carotid body glomus cells, and cold thermoreceptors, functioning as homodimers or heterodimers with TASK-1, TASK-5, or TWIK-1 (PMID:11733509, PMID:14678492, PMID:39215006, PMID:30416196). Extracellular proton sensing is mediated by His98, which upon protonation engages a cation-π interaction with Trp78 to trigger C-type inactivation at the selectivity filter, while a distinct cytoplasmic X-gate formed by M2/M4 helices provides a second gating mechanism; channel surface expression depends on PKA phosphorylation of Ser373 enabling 14-3-3 binding that masks COPI retention signals, and a COPII-dependent di-acidic ER-export motif (PMID:38630723, PMID:19703964, PMID:21357689, PMID:19139046, PMID:17547699). The channel is inhibited by direct Gαq coupling (PKC-independent) and by PKCα-mediated phosphorylation of Thr341, and activated by volatile anesthetics acting at the M4 cytoplasmic interface (PMID:17374744, PMID:11886861). Loss-of-function mutations in the maternally expressed allele—notably G236R at the X-gate—cause KCNK9 imprinting syndrome (Birk-Barel syndrome), while gain of KCNK9 copy number or expression drives oncogenic transformation requiring intact K⁺ conductance (PMID:18678320, PMID:39637865, PMID:12676587, PMID:12782791).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Establishing that KCNK9 encodes a constitutively open, pH-sensitive background K⁺ channel answered the fundamental question of what type of conductance this gene produces and identified His98 as the extracellular pH sensor.

    Evidence Heterologous expression in COS-7 cells and Xenopus oocytes with patch-clamp and H98D mutagenesis

    PMID:10734076 PMID:10747866

    Open questions at the time
    • Structural basis of His98 pH sensing not yet resolved
    • Native tissue relevance not demonstrated
  2. 2001 High

    Demonstrating that TASK-3 forms functional heterodimers with TASK-1, showing intermediate pharmacological properties, established that K2P channel diversity arises from combinatorial subunit assembly.

    Evidence Tandem-linked TASK-3/TASK-1 constructs in oocytes, pharmacological profiling with ruthenium red and pH

    PMID:11733509

    Open questions at the time
    • Stoichiometry and structural arrangement of heterodimers unknown
    • Relative abundance of homo- vs. heterodimers in native tissue not quantified
  3. 2002 High

    Identifying the VLRFLT cytoplasmic interface region as required for both volatile anesthetic activation and receptor-mediated inhibition revealed a shared gating control point, while the discovery that 14-3-3 proteins bind a C-terminal RRxSx motif to promote surface trafficking established the first trafficking mechanism for TASK-3.

    Evidence Systematic mutagenesis with halothane/TRH modulation; two-hybrid and co-IP of 14-3-3 with truncation mutants and oocyte electrophysiology

    PMID:11886861 PMID:12433946

    Open questions at the time
    • Identity of the kinase phosphorylating the 14-3-3 binding site not yet known
    • Structural mechanism of anesthetic binding not resolved
  4. 2003 High

    The demonstration that K⁺ conductance is required for TASK-3 oncogenic properties (G95E pore-dead mutant abolishes tumor formation) and that KCNK9 is amplified/overexpressed in breast cancer established it as a bona fide oncogene and linked channel function to cell survival.

    Evidence Dominant-negative G95E mutagenesis with patch-clamp, proliferation, apoptosis, and nude mouse xenograft assays; genomic amplification analysis in breast tumors

    PMID:12676587 PMID:12782791

    Open questions at the time
    • Downstream signaling pathways linking K⁺ flux to survival not identified
    • Whether oncogenic role extends beyond breast cancer not established
  5. 2004 High

    Single-channel recordings from native cerebellar granule neurons confirmed that both homomeric TASK-3 and heteromeric TASK-1/TASK-3 channels exist in the brain, resolving the native identity of background K⁺ conductances and establishing Glu70 as a key residue for zinc and divalent cation sensitivity.

    Evidence Single-channel patch-clamp in native neurons matched to cloned channels; bidirectional mutagenesis of E70/K70 with zinc pharmacology

    PMID:14678492 PMID:15282272 PMID:15284350

    Open questions at the time
    • Regional and cell-type distribution of homo- vs. heterodimers across brain not mapped
    • Physiological concentration of zinc at TASK-3-expressing synapses uncertain
  6. 2007 High

    Multiple advances resolved channel regulation and trafficking: Gαq directly inhibits TASK-3 independently of PKC (which instead opposes Gαq via Thr341 phosphorylation); a di-acidic EDE motif directs COPII-dependent ER export; the M1P1 loop containing E70 and H98 apposes the selectivity filter; and KCNK9 is maternally imprinted with the G236R loss-of-function mutation causing Birk-Barel syndrome.

    Evidence siRNA/inhibitor dissection of Gαq vs. PKC pathways; Sar1 dominant-negative and mutagenesis for COPII export; cysteine cross-linking and chimeras for pore architecture; genetic mapping and oocyte electrophysiology of G236R; allele-specific pyrosequencing in mouse and human for imprinting

    PMID:17374744 PMID:17547699 PMID:17704508 PMID:18418474 PMID:18678320

    Open questions at the time
    • Structural basis of Gαq-channel interaction not resolved
    • How imprinting at the Peg13 locus controls KCNK9 expression mechanistically unclear
  7. 2009 High

    The discovery that 14-3-3 masks a COPI-binding KRR retention motif explained how phosphorylation-dependent 14-3-3 binding controls anterograde vs. retrograde trafficking, while dual gating at the selectivity filter and a cytoplasmic inner gate was established by systematic mutagenesis.

    Evidence GST pulldown of COPI coatomer from TASK-3 C-terminal peptides; single-channel kinetic modeling with M2/M4 hinge glycine and A237T mutations

    PMID:19139046 PMID:19703964

    Open questions at the time
    • Whether COPI retrieval operates constitutively or is regulated in vivo unknown
    • Structural identity of the inner gate not visualized
  8. 2011 High

    Identification of PKA as the kinase phosphorylating Ser373 to enable 14-3-3 binding completed the trafficking signaling cascade from cAMP to channel surface expression.

    Evidence In vitro kinase assay, cell-surface expression measurement, and electrophysiology in HEK293 cells

    PMID:21357689

    Open questions at the time
    • Whether PKA-dependent trafficking is regulated physiologically in specific cell types not shown
    • Phosphatase responsible for Ser373 dephosphorylation not identified
  9. 2012 High

    TASK-3 knockout mice revealed that the channel sets resting membrane potential in adrenal glomerulosa cells and is essential for aldosterone suppression, linking channel loss to hyperaldosteronism and salt-sensitive hypertension.

    Evidence Germline Task3 KO mouse with electrophysiology in adrenal slices, Ca²⁺ imaging, hormone measurements, blood pressure

    PMID:22878402 PMID:23698720

    Open questions at the time
    • Relative contribution of plasma membrane vs. mitochondrial TASK-3 to aldosterone regulation unknown
    • Whether the phenotype reflects homo- or heteromeric channels not determined
  10. 2014 High

    TASK-3 enrichment in TRPM8⁺ cold thermoreceptors and the cold hypersensitivity of KO mice established a role in setting thermal thresholds, while Gαq/11 co-immunoprecipitation with TASK-3 in hippocampal slices confirmed the direct nature of receptor-mediated inhibition in native neurons.

    Evidence BAC-transgenic molecular profiling, KO mouse cold behavioral assays; co-IP from brain slices with neurotensin stimulation and LTP recordings

    PMID:25199828 PMID:25405940

    Open questions at the time
    • Which Gαq interface residues contact the channel not mapped
    • Whether TASK-3 is the sole cold-threshold-setting leak channel in these neurons not resolved
  11. 2017 High

    TASK-3 localization to the inner mitochondrial membrane of glomerulosa cells, confirmed by immunogold EM, expanded the channel's functional repertoire beyond plasma membrane conductance to regulation of mitochondrial membrane potential and steroidogenesis.

    Evidence Yeast two-hybrid, co-IP, electron microscopy immunogold labeling, mitochondrial membrane potential assay

    PMID:28630209

    Open questions at the time
    • How TASK-3 is targeted to mitochondria is unknown
    • Ion selectivity and gating of mitochondrial TASK-3 not characterized
  12. 2018 High

    Discovery that KCC2 directly interacts with TASK-3 and is required for its membrane expression in dentate gyrus neurons, and that TWIK-1/TASK-3 heterodimers carry outwardly rectifying currents in the same cells, revealed cell-type-specific partnership networks governing TASK-3 function.

    Evidence Co-IP from hippocampus, shRNA knockdown with patch-clamp and in vivo LFP recordings

    PMID:30416196 PMID:31269453

    Open questions at the time
    • Molecular basis of KCC2–TASK-3 interaction not mapped
    • Relative abundance of TWIK-1/TASK-3 vs. TASK-1/TASK-3 heterodimers in dentate gyrus unknown
  13. 2022 High

    Electrophysiological characterization of 15 KCNK9 imprinting syndrome variants revealed that disease arises from both gain- and loss-of-function changes, with a recurrent hotspot at Arg131, broadening the genotype-phenotype spectrum beyond the original G236R finding.

    Evidence In vitro electrophysiology of patient-derived variants, 3D molecular modeling, clinical correlation

    PMID:35698242

    Open questions at the time
    • How gain-of-function variants cause a similar clinical phenotype to loss-of-function variants not explained
    • No animal models of non-G236R variants
  14. 2023 High

    Allele-specific CTCF binding at the Peg13 DMR establishes higher-order chromatin structure that precedes and enables imprinted KCNK9 expression during neuronal differentiation, answering how epigenetic imprinting at a distal locus controls KCNK9 monoallelic expression.

    Evidence Region capture Hi-C in reciprocal hybrid mouse crosses with in vitro neuronal differentiation

    PMID:37821107

    Open questions at the time
    • Whether the same chromatin mechanism operates in non-neuronal tissues not tested
    • Specific enhancer identity not fully resolved
  15. 2024 High

    Cryo-EM structures of TASK-3 at neutral and acidic pH revealed that protonation of His98 triggers a cation-π interaction with Trp78, causing C-type inactivation via selectivity filter dilation coupled to X-gate closure; structures of the G236R disease mutant showed how the X-gate is disrupted, and TASK-5/TASK-3 functional heterodimers were demonstrated.

    Evidence Cryo-EM at multiple pH values, molecular dynamics, mutagenesis with electrophysiology; cryo-EM of G236R variant; single-channel recordings of TASK-5/TASK-3 heterodimers

    PMID:38630723 PMID:39215006 PMID:39637865

    Open questions at the time
    • No structure of TASK-3 bound to Gαq, anesthetics, or 14-3-3
    • How X-gate and selectivity filter gating are coordinated dynamically at atomic resolution remains incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of Gαq direct coupling to TASK-3, the mechanism of mitochondrial targeting and gating, the downstream signaling linking K⁺ conductance to oncogenic survival, and how both gain- and loss-of-function variants converge on the KCNK9 imprinting syndrome phenotype.
  • No structure of TASK-3 in complex with Gαq or anesthetic molecules
  • Mitochondrial targeting signal and import pathway not identified
  • Signaling cascade from K⁺ flux to apoptosis resistance unknown
  • Convergent pathophysiology of gain- and loss-of-function KIS variants unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5
Localization
GO:0005886 plasma membrane 5 GO:0005739 mitochondrion 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 3 R-HSA-9609507 Protein localization 3
Partners
COPAGNAQKCNK1KCNK15KCNK3SLC12A5YWHAZ
Complex memberships
TASK-1/TASK-3 heterodimerTASK-3 homodimerTASK-5/TASK-3 heterodimerTWIK-1/TASK-3 heterodimer

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TASK-3 (KCNK9) encodes a time-independent, noninactivating K+-selective background channel with a single-channel conductance of 27 pS at -60 mV; extracellular pH sensitivity is conferred by histidine at position 98, as H98D mutation abolishes pH sensitivity; the channel is blocked by barium, quinidine, and lidocaine. 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 Histidine 98 in the extracellular pore region of TASK-3 acts as the pH sensor; substitution with asparagine or tyrosine abolishes pH sensitivity, and the residue is located at the outer pore adjacent to the selectivity filter. Xenopus oocyte expression, two-electrode voltage clamp, site-directed mutagenesis The Journal of biological chemistry High 10734076 10747866
2001 TASK-1 and TASK-3 form functional heterodimers when co-expressed in Xenopus oocytes; heterodimeric channels show intermediate pH sensitivity and TASK-1-like ruthenium red insensitivity; tandem-linked TASK-3/TASK-1 construct recapitulates heterodimer properties; epitope-tagged channels localize primarily to the plasma membrane in mammalian cells. Xenopus oocyte co-expression, two-electrode voltage clamp, tandem construct expression, immunostaining in mammalian cells The Journal of biological chemistry High 11733509
2002 Volatile anesthetic (halothane) activation and neurotransmitter (TRH) inhibition of TASK-3 both require a six-residue sequence at the cytoplasmic C-terminus/final transmembrane domain interface (VLRFLT region); mutations in this region abolish both modalities; a large portion of the C-terminus is additionally needed for full halothane and TRH effects on TASK-3. Site-directed mutagenesis, heterologous expression, whole-cell patch-clamp in Xenopus oocytes and mammalian cells The Journal of biological chemistry High 11886861
2002 14-3-3 proteins interact with the conserved C-terminal pentapeptide motif (RRxSx) of TASK-3 and promote trafficking of the channel to the surface membrane; deletion of a single C-terminal amino acid abolishes 14-3-3 binding and strongly reduces macroscopic currents; TASK-1 and 14-3-3 co-immunoprecipitate from synaptic membrane extracts. Two-hybrid analysis, co-immunoprecipitation, Xenopus oocyte expression, surface expression assay, voltage-clamp, C-terminal truncation mutants The Journal of physiology High 12433946
2003 Ruthenium red inhibits TASK-3 by simultaneously binding to glutamate 70 of both subunits; mutation E70R or E70C abolishes inhibition; in tandem-linked homodimers, mutation of Glu70 in either subunit prevents RR action; Hill coefficient of 1 indicates a single polycationic molecule bridges both subunits; the reciprocal mutation K70E in TASK-1 confers RR sensitivity. Site-directed mutagenesis of tandem-linked and monomeric constructs, Xenopus oocyte expression, two-electrode voltage-clamp, Hill analysis Molecular pharmacology High 12606773
2003 KCNK9 is amplified (3–10-fold) in ~10% of breast tumors and overexpressed in 44%; overexpression in cell lines promotes tumor formation and confers resistance to hypoxia and serum deprivation, identifying KCNK9 as an oncogene at 8q24.3. Representational difference analysis, cell line overexpression, xenograft tumor formation assays, survival assays under hypoxia/serum deprivation Cancer cell High 12676587
2003 Potassium channel function of TASK3 is required for its oncogenic activities; a G95E pore mutation abolishes K+ current and abrogates proliferation in low serum, resistance to apoptosis, and tumor growth in nude mice; G95E acts as a dominant-negative, suppressing wild-type TASK3 current and tumorigenicity when co-expressed. Point mutagenesis (G95E), patch-clamp electrophysiology, cell proliferation and apoptosis assays, nude mouse xenograft Proceedings of the National Academy of Sciences of the United States of America High 12782791
2004 TASK-1 and TASK-3 subunits co-immunoprecipitate from membranes of transfected mammalian cells; a dominant-negative TASK-1(Y191F) construct suppresses TASK-3 currents; heteromeric TASK-1/TASK-3 channels in hypoglossal motoneurons display pH and isoflurane sensitivities matching the heterodimer pharmacological profile. Co-immunoprecipitation, dominant-negative suppression, whole-cell patch-clamp in heterologous cells and native neurons, tandem construct expression The Journal of neuroscience High 15282272
2004 Native 38 pS background K+ channels in cerebellar granule neurons consist of both homomeric TASK-3 and heteromeric TASK-1/TASK-3; heteromers are distinguished by their ruthenium red insensitivity and intermediate pH sensitivity in single-channel recordings from native patches. Single-channel patch-clamp in COS-7 cells and native cerebellar granule neurons, pharmacological dissection with ruthenium red and pH The Journal of physiology High 14678492
2004 Zinc selectively blocks TASK-3 (IC50 ~20 µM) but not TASK-1 or TASK-2; both E70 and H98 are critical for zinc block; E70K mutation abolishes zinc sensitivity of TASK-3, while the reverse K70E mutation confers zinc sensitivity to TASK-1; TASK-3/TASK-1 concatamer channels are zinc-insensitive, consistent with heterodimer formation. Site-directed mutagenesis, two-electrode voltage-clamp in Xenopus oocytes, concatamer channel expression The Journal of physiology High 15284350
2006 Glutamate 70 of TASK-3 mediates sensitivity to extracellular divalent cations (Ca2+, Mg2+); replacing E70 with lysine or arginine abolishes divalent cation sensitivity; the reverse mutation K70E in TASK-1 confers divalent cation sensitivity; spermine and ruthenium red act similarly via E70 to decrease TASK-3 open probability. Mutagenesis, single-channel patch-clamp in HEK293 cells, whole-cell recordings in thalamocortical neurons The Journal of physiology High 16513667
2006 Depolarization-induced Ca2+ entry via L-type channels activates the calcineurin pathway to upregulate TASK-3 transcription in cerebellar granule neurons; increased TASK-3 mRNA leads to elevated protein and IKso conductance, causing membrane hyperpolarization; blocking L-type Ca2+ channels or calcineurin abrogates TASK-3 expression and induces hyperexcitability. RT-PCR, pharmacological block of L-type channels (nifedipine) and calcineurin (FK506/cyclosporin A), patch-clamp electrophysiology in primary neurons The Journal of biological chemistry High 16864570
2007 Protein kinase C (PKCα) phosphorylates TASK-3 at Thr341 in the C-terminus, reducing channel current; Gαq-coupled M3 muscarinic receptor activation inhibits TASK-3 through a direct action of Gαq on the channel independent of PKC; PKC activation opposes rather than transduces Gαq-mediated inhibition. Gene silencing (siRNA), mutagenesis (T341A), whole-cell patch-clamp, Gαq antagonist (YM-254890), PKC inhibitors Molecular pharmacology High 17374744
2007 TASK-3 (KCNK9) is maternally imprinted (paternal allele silenced); a missense mutation in the maternal copy (G236R) fully abolishes TASK-3 channel current both as a homodimer and as a heterodimer with K2P3.1, causing Birk Barel mental retardation dysmorphism syndrome. Genetic mapping, DNA sequencing, Xenopus oocyte electrophysiology of mutant channels, imprinting analysis American journal of human genetics High 18678320
2007 TASK-3 KO mice show reduced sensitivity to halothane anesthetic and cannabinoid receptor agonist WIN55212-2 but unaltered responses to propofol, morphine, and lidocaine, demonstrating TASK-3's specific role in mediating select anesthetic and cannabinoid effects in vivo. Germline TASK-3 knockout mouse, pharmacological behavioral testing (halothane, cannabinoid, alpha-2 agonist, propofol, morphine, lidocaine) The Journal of pharmacology and experimental therapeutics High 17875609
2007 The M1P1 extracellular loop of TASK-3 apposes the selectivity filter; disulfide bridge formation between E70C in M1P1 and H98C in the pore confirmed proximity; M1P1 loop swap between TASK-1 and TASK-3 transfers pH sensitivity, demonstrating the loop regulates channel gating. Cysteine cross-linking with cadmium, dithiothreitol, M1P1 loop chimeras, mutagenesis, voltage-clamp in HEK cells The Journal of biological chemistry High 18417474
2007 A di-acidic EDE motif in the proximal C-terminus of TASK-3 is required for ER export and efficient surface expression; ADA mutation retains channels in the ER; Sar1H79G (GTP-restricted) also retains TASK-3 in the ER, indicating COPII-dependent export; a second DAE motif has no effect on surface expression. Luminometric surface expression assay, live-cell GFP imaging in COS-7 cells, Xenopus oocyte voltage-clamp, Sar1 dominant-negative co-expression, chimeric Kir2.1-TASK-3 C-terminus constructs Traffic (Copenhagen, Denmark) High 17547699
2007 Kcnk9 (TASK-3) expression is maternally imprinted (paternal allele silenced) in mouse embryos and adult brain; the same imprinting is confirmed in human fetal brain; the CpG islands associated with Kcnk9 are hypomethylated rather than differentially methylated, suggesting imprinting may be regulated by the nearby Peg13 DMR. Allele-specific expression quantification by pyrosequencing (QUASEP) in F1 hybrid mice and human fetal brain, CpG island methylation analysis Human molecular genetics High 17704508
2009 14-3-3 binding to the C-terminus of TASK-3 masks a tri-basic KRR retention motif; when 14-3-3 binding is disabled (by mutation), the KRR motif is exposed and binds COPI coatomer (demonstrated by GST pulldown), retaining channels in the Golgi; TASK-3 also possesses an independent N-terminal KR di-basic retention signal. GST pulldown of COPI coatomer, GFP-tagged channel localization by live imaging, dominant-negative channel co-expression, Xenopus oocyte voltage-clamp, mutational analysis The Journal of physiology High 19139046
2009 Heteromeric TASK-1/TASK-3 channels (identified by single-channel conductance and pharmacological profile) constitute ~75% of the oxygen-sensitive TASK-like background K+ conductance in rat carotid body glomus cells; hypoxia inhibits TASK-1/3 heteromers in native glomus cells. Single-channel outside-out and cell-attached patch-clamp in isolated glomus cells, comparison with cloned TASK-1, TASK-3, and TASK-1/3 tandem channels, ruthenium red and methanandamide pharmacology The Journal of physiology High 19403596
2009 TASK-3 gating occurs at both the selectivity filter (pH-sensitive) and a cytoplasmic inner gate; voltage-dependent gating reflects opening at the cytoplasmic mouth via M2 and M4 helix movements; mutations A237T (M4) and N133A (M2) increase open probability and shift voltage dependence; hinge glycines G117A and G231A reduce open probability, and none of these mutants alter pH sensitivity. Two-electrode voltage-clamp, single-channel patch-clamp, mutagenesis, kinetic modeling The Journal of physiology High 19703964
2011 Protein kinase A (PKA/cAMP-dependent kinase) phosphorylates Ser373 in the C-terminus of TASK-3 (K2P9.1); this phosphorylation enables 14-3-3 binding and promotes forward trafficking of TASK-3 to the plasma membrane; in vitro phosphorylation assays and cell-surface expression measurements confirm PKA as the relevant kinase. In vitro kinase phosphorylation assay, cell surface expression assay (GFP-tagged channels), whole-cell patch-clamp in HEK293 cells, bioinformatic candidate kinase identification The Journal of biological chemistry High 21357689
2011 Covalent modification of Met159 in TASK-3 by NEM (M159C + NEM) irreversibly activates the channel and renders it resistant to inhibition by both acidic pH and active Gαq; bulky hydrophobic substitutions M159W and M159F mimic this effect; single-subunit modification in wild-type/M159C tandem dimers is sufficient for channel activation, with cross-talk between subunits. Cysteine-selective alkylation (NEM), site-directed mutagenesis, Ussing chamber ion flux in Fischer rat thyroid cells, tandem dimer constructs Molecular pharmacology High 22147752
2012 N-linked glycosylation at the conserved site in TASK-3 (K2P9.1) mildly reduces channel surface expression when disrupted, but has no detectable functional consequence on channel current, distinguishing TASK-3 from TASK-1 where glycosylation more strongly regulates surface density. Flow cytometry surface expression, patch-clamp electrophysiology, site-directed mutagenesis of glycosylation site, tunicamycin treatment The Journal of biological chemistry Medium 23250752
2012 Task3 knockout mice show depolarized adrenal glomerulosa cells (-52 mV vs. -79 mV in WT), abnormal Ca2+ signaling in glomerulosa cells, failure to suppress aldosterone under high Na+/low K+ diet, elevated aldosterone-renin ratio, and consequent salt-sensitive hypertension (~10 mmHg increase). Germline Task3 KO mouse, whole-cell electrophysiology in adrenal slices, Ca2+ imaging, adrenal aldosterone secretion assays, blood pressure measurement Endocrinology High 22878402
2013 G236R mutant TASK-3 (Birk Barel mutation) produces a small, inwardly rectifying current rather than the normal outward K+ current; mutant channels are differentially sensitive to extracellular acidification, zinc, and Gαq-coupled muscarinic receptor activation compared to WT; an additional A237T gain-of-function mutation or flufenamic acid can restore outward current through G236R channels. Whole-cell voltage-clamp in transfected cells, pharmacological profiling, double mutagenesis Molecular pharmacology High 24342771
2013 Neonatal Task3 KO mice display severe hyperaldosteronism with markedly elevated aldosterone, corticosterone, and progesterone; the most strongly upregulated gene in KO adrenals is renin, which is expressed in zona fasciculata, indicating activation of an intra-adrenal renin-angiotensin system as a consequence of Task3 loss. Germline Task3 KO mouse, plasma hormone measurements, real-time PCR, immunofluorescence for renin Endocrinology High 23698720
2014 TASK-3 channels are highly enriched in a subpopulation of TRPM8-expressing cold thermoreceptor neurons; TASK-3 blockade or TASK-3 KO lowers cold threshold and produces hypersensitivity to cold, demonstrating TASK-3 sets the thermal threshold of cold receptors. BAC transgenesis, FACS purification, molecular profiling, TASK-3 KO mouse, pharmacological blockade, cold behavioral assays Cell reports High 25199828
2014 Neurotensin acting via NTS1 receptors inhibits TASK-3 K+ channels in dentate gyrus granule cells through Gαq/11 in a PLC/IP3/PKC-independent manner; co-immunoprecipitation shows direct association of Gαq/11 with TASK-3 upon NTS1 activation; this inhibition depolarizes granule cells and facilitates LTP at perforant path synapses. Whole-cell patch-clamp, co-immunoprecipitation from brain slices, pharmacological dissection, LTP recording in hippocampal slices Cerebral cortex High 25405940
2015 Breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 by binding at a common site within the intracellular pore region; mutations L122D and G236D increase PKTHPP IC50 >1000-fold; the Birk Barel G236R disease mutation maps to this drug-binding site. Alanine-scan and charge-reversal mutagenesis, Ussing chamber ion flux in Fischer rat thyroid cells expressing TASK-3, homology modeling and molecular docking Molecular pharmacology High 26268529
2016 A monoclonal antibody (Y4) targeting the TASK-3 extracellular domain induces channel internalization in KCNK9-expressing carcinoma cells, reducing cell viability; systemic Y4 administration inhibits lung cancer xenograft growth and breast cancer metastasis in mice through cell-autonomous and immune-dependent cytotoxicity. Monoclonal antibody development, channel internalization assay, cell viability assay, xenograft and metastasis mouse models Nature communications High 26842342
2017 TASK-3 channels are present in the inner mitochondrial membrane of aldosterone-producing zona glomerulosa cells; yeast 2-hybrid, co-immunoprecipitation, and electron microscopy confirm mitochondrial localization; mitochondrial TASK-3 regulates mitochondrial morphology, mitochondrial membrane potential, and aldosterone production. Yeast two-hybrid, co-immunoprecipitation, electron microscopy immunogold labeling, mitochondrial membrane potential assay, aldosterone secretion measurements in KO cells Hypertension High 28630209
2017 Terbinafine selectively activates TASK-3 (pEC50 6.2 in thallium flux assay) but not TASK-1, TASK-2, TREK2, THIK1, TWIK1, or TRESK; activation confirmed by whole-cell patch-clamp; terbinafine also potentiates the disease-associated G236R TASK-3 mutant current. Thallium flux assay, whole-cell patch-clamp electrophysiology, selectivity screening across K2P channels Biochemical and biophysical research communications High 28882594
2018 KCC2 (K-Cl cotransporter) interacts directly with TASK-3 (KCNK9) channels and is required for their membrane expression; KCC2 knockdown in rat dentate gyrus downregulates TASK-3 membrane localization, depolarizes resting membrane potential, and increases neuronal excitability, altering dentate gyrus rhythmogenesis. Co-immunoprecipitation, KCC2 knockdown (shRNA), patch-clamp electrophysiology, in vivo LFP recordings in dentate gyrus Cell reports High 31269453
2018 TWIK-1 and TASK-3 form heterodimeric channels in dentate gyrus granule cells; co-immunoprecipitation from mouse hippocampus and COS-7 cells confirms association; shRNA-mediated silencing demonstrates these heterodimers carry outwardly rectifying currents and contribute to intrinsic excitability; NT-NTSR1 signaling depolarizes granule cells by inhibiting TWIK-1/TASK-3 heterodimers. Co-immunoprecipitation, shRNA knockdown, whole-cell patch-clamp, neurotensin pharmacology in brain slices Experimental & molecular medicine High 30416196
2020 Withaferin A inhibits TASK-3 channel activity in a dose-dependent, voltage-independent manner; molecular docking and mutagenesis identify binding residues F125 and L197 in the channel pore; F125A, L197V, and F125A-L197V mutations markedly reduce WFA inhibition; WFA cytotoxicity on MDA-MB-231 breast cancer cells depends on TASK-3 expression. Whole-cell patch-clamp, molecular docking, site-directed mutagenesis, shRNA knockdown, cell viability assay Biomedicine & pharmacotherapy High 32563149
2022 KCNK9 imprinting syndrome variants cause both gain-of-function and loss-of-function changes in TASK-3 conductance, but the most consistent functional impact is altered channel regulation; a recurrent mutational hotspot at p.Arg131 was identified in addition to G236R. In vitro electrophysiology of 15 novel variants, 3D molecular modeling, sequence-based analysis, clinical genetics Genome medicine High 35698242
2023 Imprinted chromatin structure at the Peg13-Kcnk9 locus is established by allele-specific CTCF binding to the Peg13 DMR; allelic higher-order chromatin structure (mapped by region capture Hi-C) precedes imprinted expression of Kcnk9 during neuronal differentiation; activation of a distal enhancer induces imprinted Kcnk9 expression only in the presence of this allelic chromatin structure. Region capture Hi-C in reciprocal hybrid mouse crosses, in vitro neuron differentiation, allele-specific chromatin analysis, CTCF binding analysis Genes & development High 37821107
2024 Cryo-EM structures of human TASK-3 at neutral and acidic pH reveal that extracellular acidification induces C-type inactivation characterized by selectivity filter dilation and simultaneous hydrophobic gate closure; His98 protonation shifts the conformational equilibrium toward C-type inactivation via a cation-π interaction with Trp78, validated by molecular dynamics and mutagenesis. Cryo-EM structure determination at neutral and acidic pH, molecular dynamics simulations, site-directed mutagenesis with electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 38630723
2024 Cryo-EM structures of both human TASK-1 and TASK-3 (including the G236R KIS variant) resolved; structural analysis reveals a conserved lower X-gate as a hotspot for disease-causing mutations; G236R structural defect provides mechanistic insight into how channel gating is disrupted in KCNK9 imprinting syndrome. Cryo-EM structure determination, functional electrophysiology of X-gate mutants, structural comparison of WT and G236R TASK-3 Structure (London, England : 1993) High 39637865
2024 TASK-5 (KCNK15) forms functional heterodimers with TASK-3; TASK-5 alone is non-functional but heteromeric TASK-5/TASK-3 complexes at the plasma membrane show altered single-channel conductance, modified Gq-coupled receptor inhibition, and altered sensitivity to TASK modulators compared to TASK-3 homodimers. Heterologous co-expression, single-channel patch-clamp, Gq receptor pharmacology, surface expression assays Nature communications High 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 269 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 171 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
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
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 142 18678320
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 115 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
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
2018 TWIK-1/TASK-3 heterodimeric channels contribute to the neurotensin-mediated excitation of hippocampal dentate gyrus granule cells. Experimental & molecular medicine 62 30416196
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
2014 Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index. PLoS genetics 50 25078964
2019 KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels. Cell reports 49 31269453
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 41 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
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
2015 TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes. Journal of molecular and cellular cardiology 35 25655935
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 30 27151206
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
2006 Membrane potential-regulated transcription of the resting K+ conductance TASK-3 via the calcineurin pathway. The Journal of biological chemistry 29 16864570
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 26 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
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
2002 Tandem pore domain K(+)-channel TASK-3 (KCNK9) and idiopathic absence epilepsies. American journal of medical genetics 21 11857586
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 14 31977249
2008 Altered neuronal expression of TASK1 and TASK3 potassium channels in rodent and human autoimmune CNS inflammation. Neuroscience letters 14 18824070
2019 Novel variant in the KCNK9 gene in a girl with Birk Barel syndrome. European journal of medical genetics 13 30690205
2022 Tandem pore domain acid-sensitive K channel 3 (TASK-3) regulates visual sensitivity in healthy and aging retina. Science advances 12 36070380
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
2022 Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. Genome medicine 11 35698242
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
2024 Potassium channel TASK-5 forms functional heterodimers with TASK-1 and TASK-3 to break its silence. Nature communications 9 39215006
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
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
2006 The background K(+) channel TASK-3 is regulated at both the transcriptional and post-transcriptional levels. Biochemical and biophysical research communications 6 16925981