Affinage

KCNK3

Potassium channel subfamily K member 3 · UniProt O14649

Length
394 aa
Mass
43.5 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNK3 (TASK-1) is a two-pore-domain background potassium channel that sets the resting membrane potential of neurons, cardiomyocytes, vascular smooth muscle, and endocrine cells, where its constitutive K+ leak constrains excitability, Ca2+ entry, and downstream secretory and proliferative responses (PMID:15282272, PMID:16574908, PMID:25849724). It assembles as a homodimer or as TASK-1/TASK-3 heterodimers that produce native background currents of intermediate pH and pharmacological sensitivity in motoneurons, cerebellar granule cells, carotid body glomus cells, and atrial myocytes (PMID:11733509, PMID:15282272, PMID:14678492, PMID:19403596, PMID:25655935). Channel gating is governed by a lower 'X-gate' formed by the crossed C-terminal M4 helices (residues 243-248), which controls open probability and serves as the convergence point for volatile anesthetics and GPCR signals; high-affinity inhibitors bind below the selectivity filter and are trapped in the vestibule by the closed gate (PMID:32499642, PMID:11886861). Conduction and proton sensing depend on the pore-flanking histidine H98, which both reports extracellular pH and shapes selectivity-filter structure (PMID:20410120, PMID:15611021). TASK-1 activity is extensively tuned by signaling: Gq-coupled receptors inhibit it through phospholipase C (PMID:11443069), endothelin-1 inhibits it via PKC- and Rho-kinase-dependent phosphorylation of Ser393 (and Ser336 for ETA-selective regulation) leading to depolarization (PMID:19188660, PMID:21838752), PKG raises proton-binding Kd to upregulate current (PMID:20410120), and PKA-mediated treprostinil signaling activates it (PMID:16574908). Surface density is set by a trafficking program in which phosphorylation of Ser393 by PKA licenses 14-3-3 binding to suppress COPI-mediated ER retention and promote forward transport, with a second phosphosite acting as a switch and p11 (S100A10) modulating delivery (PMID:21357689, PMID:17908283, PMID:26743085); PKC triggers 14-3-3β-dependent endocytosis through a dedicated endocytic motif (PMID:22846993), syntaxin-8 drives clathrin-mediated cooperative internalization from early endosomes (PMID:24743596), and N-linked glycosylation stabilizes channels at the plasma membrane (PMID:23250752). Through this regulatory architecture TASK-1 contributes to oxygen sensing in the carotid body (PMID:19403596), pulmonary vascular tone where loss-of-function impairs hyperpolarization and promotes PASMC proliferation (PMID:16574908, PMID:30365877), glucagon secretion in pancreatic α-cells (PMID:25849724), and aldosterone production in adrenal glomerulosa cells (PMID:19878209). Gain-of-function mutations clustered at the X-gate produce constitutively overactive, GPCR-unresponsive channels causing a developmental disorder with sleep apnea, while loss-of-function missense variants (G106R, L214R) that retain normal surface localization underlie heritable pulmonary arterial hypertension (PMID:36195757, PMID:30365877).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2001 High

    Established that TASK-1 does not act alone but coassembles with TASK-3 into heterodimeric channels, explaining the intermediate biophysical properties of native background currents.

    Evidence Xenopus oocyte electrophysiology with tandem TASK-3/TASK-1 constructs and pharmacological discrimination

    PMID:11733509

    Open questions at the time
    • Stoichiometry and subunit arrangement not resolved at this stage
    • Physiological tissues where heterodimers dominate not yet defined
  2. 2001 High

    Defined how Gq-coupled receptors inhibit TASK-1, showing the signal proceeds through phospholipase C rather than canonical downstream second messengers.

    Evidence Two-electrode voltage clamp in oocytes with GTPγS, U-73122, and PLC-β2 co-expression rescue

    PMID:11443069

    Open questions at the time
    • Direct molecular effector linking PLC to the channel not identified
    • PIP2 versus other lipid involvement unresolved here
  3. 2002 High

    Mapped the channel region required for both anesthetic activation and neurotransmitter inhibition to a six-residue cytoplasmic stretch immediately after M4, localizing modulatory control to the proximal C-terminus.

    Evidence Site-directed mutagenesis and voltage-clamp in oocytes using multiple modulatory agents

    PMID:11886861

    Open questions at the time
    • How this region couples to the gate was not structurally explained
    • Putative phosphosite shown dispensable but mechanism left open
  4. 2004 High

    Confirmed physical TASK-1/TASK-3 coassembly and demonstrated its functional contribution to native background current in motoneurons and cerebellar granule cells.

    Evidence Co-IP, dominant-negative TASK-1(Y191F), single-channel and slice patch-clamp with ruthenium red and pH discrimination

    PMID:14678492 PMID:15282272

    Open questions at the time
    • Proportion of homo- versus heterodimers tissue-by-tissue incompletely quantified
    • Assembly determinants on the subunits not mapped
  5. 2004 Medium

    Showed that the pore-flanking histidine H98 is dual-purpose, sensing extracellular pH while also shaping selectivity-filter structure and ion permeation.

    Evidence H98 mutagenesis with ion selectivity and Ba2+ block measurements in oocytes

    PMID:15611021

    Open questions at the time
    • Single lab, single study
    • Structural basis for filter coupling not directly visualized
  6. 2004 Medium

    Identified TASK-1 as an HIV-1 Vpu interaction partner, with reciprocal functional antagonism between channel and viral protein.

    Evidence Co-IP from cells and lymphoid tissue, current recordings, and HIV-1 particle-release assays

    PMID:15099524

    Open questions at the time
    • Single lab
    • Physiological relevance to infection in vivo not established
  7. 2006 High

    Placed TASK-1 at the center of pulmonary vascular membrane potential control, showing its leak current mediates responses to acidosis, hypoxia, and prostacyclin analogs.

    Evidence siRNA knockdown and whole-cell patch-clamp in primary human PASMCs with PKA pathway pharmacology

    PMID:16574908

    Open questions at the time
    • Direct molecular link from PKA to channel activation not mapped here
    • Hypoxia-sensing mechanism left unresolved
  8. 2007 High

    Defined the forward-trafficking logic of TASK-1, in which 14-3-3 binding overrides dual COPI-mediated ER retention to permit surface delivery, with p11 as a tissue-selective modulator.

    Evidence Binding assays, co-IP, immunofluorescence localization, and electrophysiology in mammalian cells

    PMID:17908283

    Open questions at the time
    • Kinase generating the 14-3-3 signal not yet identified at this stage
    • Tissue specificity of p11 effect not fully delineated
  9. 2009 High

    Dissected endothelin-1 inhibition of TASK-1 into convergent kinase pathways, identifying Ser393 as the critical phosphoacceptor and Ser336 as an ETA-selective site.

    Evidence Patch-clamp in hPASMCs and oocytes, Ser393/Ser336 mutagenesis, Rho-kinase and PLC/PKC pharmacology, perfused lung

    PMID:19188660 PMID:21838752

    Open questions at the time
    • Whether PKC and Rho-kinase act on the same or distinct residues partly unresolved
    • In vivo contribution to PAH not directly tested here
  10. 2009 Medium

    Extended TASK-1's role to endocrine control, placing it upstream of Ca2+/CaMK-driven aldosterone production in adrenal glomerulosa cells.

    Evidence siRNA knockdown in H295R cells with Ca2+ imaging, CaMK inhibition, and steroidogenesis assays

    PMID:19878209

    Open questions at the time
    • Single lab in a cell line
    • In vivo adrenal phenotype not established here
  11. 2009 High

    Identified heteromeric TASK-1/TASK-3 as the dominant oxygen-sensitive background channel in carotid body glomus cells, linking the channel to peripheral chemoreception.

    Evidence Single-channel patch-clamp in isolated glomus cells versus cloned channels with multiple pharmacological discriminators

    PMID:19403596

    Open questions at the time
    • Molecular identity of the hypoxia transducer acting on the channel unknown
    • Direct versus indirect O2 sensing unresolved
  12. 2010 Medium

    Revealed a PKG-dependent mechanism that upregulates TASK-1 by lowering proton-binding affinity, acting through the H98 pH sensor.

    Evidence PKG-loaded HEK293 cells and identified cholinergic neurons with H98 mutagenesis

    PMID:20410120

    Open questions at the time
    • Direct phosphorylation site for PKG effect not mapped
    • Single lab
  13. 2011 High

    Identified PKA as the kinase that phosphorylates Ser393 to enable 14-3-3 binding and forward transport, connecting cAMP signaling to channel surface density.

    Evidence In vitro kinase assays and cell-surface flow cytometry of GFP-channels, ruling out RSK and PKC

    PMID:21357689

    Open questions at the time
    • Subcellular compartment of PKA action not defined
    • Cross-talk with the inhibitory ET-1/Ser393 axis not reconciled
  14. 2012 High

    Showed that PKC drives rapid 14-3-3β-dependent endocytosis of TASK-1 via a dedicated endocytic motif, establishing a regulated removal arm complementing forward trafficking.

    Evidence Patch-clamp in granule neurons and cell lines, 14-3-3β siRNA, endocytic motif mutagenesis, surface biotinylation

    PMID:22846993

    Open questions at the time
    • Endocytic adaptor machinery not fully defined here
    • Relationship to PKC-mediated current inhibition not separated
  15. 2012 Medium

    Established N-linked glycosylation as a determinant of TASK-1 surface stability rather than secretory transit.

    Evidence Patch-clamp, surface flow cytometry, glycosite mutagenesis, and glycosylation inhibitors

    PMID:23250752

    Open questions at the time
    • Single lab
    • Mechanism of surface stabilization by glycan not defined
  16. 2012 Medium

    Tested and rejected ROS as the inhibitory hypoxic signal for TASK channels, refining models of chemoreceptor oxygen sensing.

    Evidence Inside-out and outside-out patch-clamp across multiple native cell types and cloned channels with superoxide generation

    PMID:23007462

    Open questions at the time
    • Identity of the true hypoxic signal remains unknown
    • Negative finding from a single lab
  17. 2014 High

    Demonstrated that syntaxin-8 physically binds TASK-1 and promotes clathrin-mediated cooperative endocytosis from early endosomes, adding a SNARE-dependent route of surface removal.

    Evidence Co-IP, TIRF imaging of clathrin/channel/syntaxin-8 vesicles, endosomal colocalization, and dual endocytosis-signal mutagenesis

    PMID:24743596

    Open questions at the time
    • Single lab
    • How syntaxin-8 and 14-3-3β pathways are coordinated unknown
  18. 2014 Medium

    Showed that loss of TASK-1 current in chronic atrial fibrillation arises from phosphorylation-dependent inhibition rather than protein downregulation, distinguishing functional from expression-level regulation in disease.

    Evidence Patch-clamp of human and canine AF atrial myocytes with intrapipette phosphatase rescue and total-protein westerns

    PMID:25437921

    Open questions at the time
    • Responsible kinase/phosphosite in AF not identified
    • Single lab
  19. 2015 High

    Established physiological roles for TASK-1 in metabolic and endocrine tissues, controlling glucagon secretion in α-cells and β-adrenergic thermogenesis in brown adipose tissue.

    Evidence α-cell-specific and global Task1 knockout mice, patch-clamp, Ca2+ imaging, secretion and thermogenesis assays with MR pharmacology

    PMID:25849724 PMID:26527067

    Open questions at the time
    • BAT phenotype mechanism via mineralocorticoid receptor is correlative
    • Cell-autonomous versus systemic contributions to thermogenesis not fully separated
  20. 2015 Medium

    Reinforced the heteromeric identity of native cardiac background channels and showed TASK-1/TASK-3 heteromers dominate surface expression with altered blocker sensitivity.

    Evidence Single-channel patch-clamp of human atrial myocytes plus tandem/co-expression constructs in HEK293 and oocytes

    PMID:25655935

    Open questions at the time
    • Single lab
    • In vivo cardiac consequence of heteromer dominance not tested
  21. 2016 High

    Resolved the trafficking switch logic, showing dual phosphorylation can either license or block 14-3-3 binding, and that TASK-1 binds 14-3-3 ~100-fold weaker than TASK-3.

    Evidence Quantitative binding assays with all 14-3-3 isoforms, phosphopeptide competition, co-IP, and electrophysiology

    PMID:26743085

    Open questions at the time
    • Kinases targeting the second serine in vivo not identified
    • Functional consequence of weaker 14-3-3 affinity for heterodimers unresolved
  22. 2018 Medium

    Showed that PAH-associated G106R and L214R variants abolish current despite normal surface trafficking, defining a conduction/gating loss-of-function mechanism resistant to pharmacological activation.

    Evidence Patch-clamp, confocal microscopy, and in-cell/on-cell westerns with multiple activators in tsA201 cells

    PMID:30365877

    Open questions at the time
    • Structural basis of current loss not directly visualized
    • Single lab
  23. 2019 Medium

    Defined a transcriptional-to-surface regulatory axis (Sp1→p11→TASK-1) that lowers channel surface expression to drive neuronal hyperexcitability, implicated in ALS motor neuron degeneration.

    Evidence Sp1/p11 siRNA and overexpression, SOD1-G93A mice, patch-clamp, and surface immunofluorescence

    PMID:31439839

    Open questions at the time
    • Single lab
    • Direct causality of TASK-1 reduction in human ALS not established
  24. 2019 Medium

    Localized the doxapram/GAL-054 inhibitory site to the intracellular pore-lining region, distinct from the extracellular zinc site, with enantioselective potency.

    Evidence Whole-cell patch-clamp, pore-lining mutagenesis, C-terminus deletion, and chiral enantiomer comparison

    PMID:31423744

    Open questions at the time
    • Atomic binding pose not resolved here
    • Single lab
  25. 2020 High

    Provided the structural basis of gating by revealing the lower X-gate formed by crossed M4 helices and showing high-affinity inhibitors are trapped beneath the closed gate, unifying gating, anesthetic response, and pharmacology.

    Evidence X-ray crystallography of TASK-1 alone and with inhibitors, X-gate mutagenesis, and functional electrophysiology

    PMID:32499642

    Open questions at the time
    • How GPCR/anesthetic signals physically move the gate not fully resolved
    • Heterodimer structure not determined
  26. 2022 High

    Linked X-gate-clustered gain-of-function KCNK3 mutations to a developmental disorder with sleep apnea, showing constitutively overactive, GPCR-unresponsive channels that retain pharmacological inhibitor sensitivity.

    Evidence Patch-clamp of patient mutations in heterologous cells, GPCR modulation assays, inhibitor screening, and clinical genetics

    PMID:36195757

    Open questions at the time
    • In vivo neuronal circuit consequences not directly demonstrated
    • Therapeutic inhibitor efficacy in patients not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the upstream signal coupling hypoxia to TASK-1 inhibition, and how diverse GPCR/anesthetic inputs are mechanically transmitted to the X-gate, remain unresolved.
  • No molecular hypoxia transducer identified
  • No structural mechanism connecting C-terminal modulatory region to X-gate movement
  • Heterodimer structure and regulation incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 3
Localization
GO:0005886 plasma membrane 7 GO:0005783 endoplasmic reticulum 2 GO:0005768 endosome 1
Pathway
R-HSA-9609507 Protein localization 5 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-397014 Muscle contraction 2
Partners
KCNK9S100A10STX8VPUYWHAB
Complex memberships
TASK-1/TASK-3 heterodimer

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TASK-1 and TASK-3 form functional heterodimers when coexpressed in Xenopus oocytes, producing channels with intermediate pH sensitivity and ruthenium-red insensitivity characteristic of TASK-1 homodimers; tandem-linked TASK-3/TASK-1 constructs recapitulate this behavior and show intermediate inhibition by AT1a angiotensin II receptor stimulation. Xenopus oocyte electrophysiology, tandem-construct expression, epitope-tagged channel localization in mammalian cells The Journal of biological chemistry High 11733509
2002 Both volatile anesthetic activation (halothane) and neurotransmitter/TRH inhibition of TASK-1 require a six-residue sequence at the cytoplasmic C-terminus immediately following the last transmembrane domain (M4); mutations in this region virtually abolish both effects. A potential phosphorylation site within this region is not required for modulation. Site-directed mutagenesis, two-electrode voltage-clamp in Xenopus oocytes, tandem heterodimer constructs The Journal of biological chemistry High 11886861
2001 TASK-1 is inhibited by Gq-coupled receptor stimulation (LPA, ANG II via AT1a, carbachol via M1) through a phospholipase C (PLC)-dependent mechanism; downstream PLC signals (IP3, Ca2+, DAG) are not the mediators. Gi-coupled M2 receptor activation has minimal effect unless PLC-β2 is co-expressed, implicating PLC activity (not Gi per se) as the key step. Xenopus oocyte two-electrode voltage clamp, GTPγS injection, PLC inhibitor U-73122, co-expression of receptor and PLC-β2 constructs American journal of physiology. Cell physiology High 11443069
2004 TASK-1 and TASK-3 subunits coassemble into heterodimeric channels in mammalian cells, as shown by co-immunoprecipitation; a dominant-negative TASK-1(Y191F) construct suppresses TASK-3 currents. Heteromeric TASK-1/TASK-3 channels in hypoglossal motoneurons have pH sensitivity (~pK 7.3) and isoflurane sensitivity intermediate between the two homomers, providing a substantial component of native background K+ current. Co-immunoprecipitation from transfected mammalian cell membranes, dominant-negative expression, tandem-construct electrophysiology, patch-clamp in hypoglossal motoneuron slices, ruthenium red pharmacology The Journal of neuroscience : the official journal of the Society for Neuroscience High 15282272
2004 HIV-1 Vpu physically interacts with TASK-1 in cultured cells and in AIDS lymphoid tissues; Vpu abolishes TASK-1 current, while TASK-1 overexpression impairs Vpu-mediated viral particle release. The N-terminal 40 amino acids of TASK-1 (homologous to Vpu) can enhance HIV-1 particle release. Co-immunoprecipitation from cultured cells and lymphoid tissue, electrophysiological recording of TASK-1 currents, HIV-1 particle release assay Molecular cell Medium 15099524
2006 In human pulmonary artery smooth muscle cells (PASMCs), TASK-1 controls resting membrane potential; siRNA knockdown depolarizes PASMCs and abolishes sensitivity to anandamide, acidosis, alkalosis, hypoxia, and treprostinil. Treprostinil activates TASK-1 via PKA-dependent phosphorylation. Whole-cell patch-clamp, TASK-1 siRNA knockdown in primary human PASMCs, membrane potential measurements Circulation research High 16574908
2007 Forward trafficking of K2P3.1 (TASK-1) to the plasma membrane requires 14-3-3 protein binding, which suppresses COPI-mediated ER retention. The channel uses two separate COPI-binding sites (N- and C-termini); disrupting either interferes with ER retention. p11 binds the C-terminal retention motif in a 14-3-3-dependent manner and modulates forward transport in a subset of tissues. Biochemical binding assays, co-immunoprecipitation, electrophysiology, subcellular localization by immunofluorescence in mammalian cells Traffic (Copenhagen, Denmark) High 17908283
2009 TASK-1 current in human PASMCs is inhibited by ET-1 through ETA receptors acting via phospholipase C, PIP2, DAG, and protein kinase C, leading to phosphorylation of TASK-1 and membrane depolarization. siRNA knockdown of TASK-1 abolishes ET-1–induced depolarization. Whole-cell patch-clamp in primary hPASMCs, TASK-1 siRNA, pharmacological dissection of PLC/PKC pathway, isolated perfused mouse lung American journal of respiratory cell and molecular biology High 19188660
2009 TASK-1 current in heterologous systems and human PASMCs is inhibited by ET-1 through both ETA (IC50=0.08 nM) and ETB (IC50=0.23 nM) receptors via Rho kinase signaling. Phosphorylation of Ser393 on TASK-1 is required for ETA- and ETB-mediated inhibition; Ser336 mutation selectively attenuates ETA-dependent regulation only. Two-electrode voltage clamp in Xenopus oocytes, whole-cell patch-clamp in hPASMCs, site-directed mutagenesis of Ser393 and Ser336, Rho kinase inhibitor Y-27632 British journal of pharmacology High 21838752
2009 TASK-1 channels are functionally expressed in adrenal glomerulosa H295R cells; siRNA knockdown of TASK-1 increases intracellular Ca2+, activates calmodulin kinase (CaMK), upregulates StAR and CYP11B2 expression, and stimulates pregnenolone and aldosterone production, placing TASK-1 upstream of Ca2+/CaMK aldosterone regulation. siRNA knockdown in H295R cells, Fluo-4 Ca2+ imaging, CaMK pharmacological inhibition, steroid production assays, microarray Clinical endocrinology Medium 19878209
2011 PKA (cAMP-dependent protein kinase) is the kinase responsible for phosphorylating Ser393 of K2P3.1 (TASK-1), enabling 14-3-3 binding and forward transport to the plasma membrane; in vitro phosphorylation assays and cell-surface expression assays confirmed PKA as the relevant kinase over RSK and PKC. In vitro phosphorylation assays, electrophysiology of HEK293-expressed K2P3.1, cell-surface GFP-channel flow cytometry assays, bioinformatics The Journal of biological chemistry High 21357689
2012 PKC activation (by phorbol esters or group I mGluR stimulation) acutely internalizes TASK-1 (KCNK3) from the cell surface via a mechanism requiring both 14-3-3β and a novel endocytic motif in the channel; depleting either 14-3-3β or ablating the endocytic motif abolishes PKC-regulated trafficking. Patch-clamp in cerebellar granule neurons and cell lines, phorbol ester treatment, mGluR agonist, 14-3-3β siRNA depletion, endocytic motif mutagenesis, surface biotinylation The Journal of biological chemistry High 22846993
2012 N-linked glycosylation of K2P3.1 (TASK-1) at its conserved glycan acceptor site is required for normal cell-surface expression; disruption of glycosylation reduces TASK-1 current and decreases the number of channels at the plasma membrane without grossly altering secretory pathway passage. Patch-clamp electrophysiology, flow cytometry of surface channels, mutagenesis of N-glycosylation site, glycosylation inhibitors, reduced glucose culture The Journal of biological chemistry Medium 23250752
2014 The endosomal SNARE protein syntaxin-8 physically interacts with TASK-1 and promotes clathrin-mediated cooperative endocytosis, reducing TASK-1 surface expression ~fourfold; TASK-1 colocalizes with syntaxin-8 in early endosomes (2xFYVE/rab5-positive). Both an endocytosis signal in TASK-1 and one in syntaxin-8 are required for this effect. Co-expression in Xenopus oocytes and mammalian cells, co-immunoprecipitation, TIRF microscopy of clathrin/TASK-1/syntaxin-8 vesicles, endosomal colocalization, endocytosis signal mutagenesis Molecular biology of the cell High 24743596
2016 14-3-3 binding to the TASK-1 C-terminal trafficking control region is controlled by dual phosphorylation: phosphorylation of the primary serine prevents COPI binding even in the absence of 14-3-3, while phosphorylation of a second serine residue inhibits 14-3-3 binding, creating a switch that can either promote or inhibit surface expression depending on which site is phosphorylated. 14-3-3 affinities for TASK-1 are ~100-fold lower than for TASK-3. Quantitative binding assays with all human 14-3-3 isoforms, phosphopeptide competition, co-immunoprecipitation, electrophysiology Journal of cell science High 26743085
2004 In cerebellar granule cells, native 38-pS background K+ channels consist of both homomeric TASK-3 and heteromeric TASK-1/TASK-3, distinguished by differential sensitivity to ruthenium red and extracellular pH; ~58% of patches show ruthenium-red-insensitive (TASK-1/TASK-3-like) conductance. Single-channel patch-clamp in cerebellar granule neurons and COS-7 cells expressing cloned channels, ruthenium red pharmacology, pH sensitivity The Journal of physiology High 14678492
2010 PKG activation dynamically upregulates TASK-1 leak currents in cholinergic basal forebrain neurons by reducing the channel's proton-binding affinity (increasing Kd for H+), shifting pH sensitivity; this modulation requires the extracellular pH sensor H98, as H98 mutation abolishes PKG-dependent regulation. Patch-clamp in PKG-loaded HEK293 cells expressing TASK-1, site-directed mutagenesis of H98, patch-clamp in identified cholinergic basal forebrain neurons The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 20410120
2004 Pore-flanking histidine H98 of TASK-1 contributes to both pH sensing and to the structure of the ion conduction pathway; H98D and H98N mutations reduce K+ selectivity, increase Rb+ permeability, and alter the voltage-dependence of Ba2+ block, indicating that H98 influences selectivity filter structure. Site-directed mutagenesis, two-electrode voltage clamp in Xenopus oocytes, ion selectivity and Ba2+/Cs+ block measurements The Journal of physiology Medium 15611021
2009 Heteromeric TASK-1/TASK-3 channels are the predominant (~75%) oxygen-sensitive background K+ channel in rat carotid body glomus cells, identified by single-channel conductance profiling and differential sensitivity to Mg2+, ruthenium red, and methanandamide; hypoxia inhibits TASK-1/TASK-3-like channels in these cells. Single-channel outside-out and cell-attached patch-clamp in isolated carotid body cells and HeLa cells expressing cloned channels, Mg2+ removal conductance shifts, ruthenium red pharmacology The Journal of physiology High 19403596
2015 TASK-1 channels expressed in pancreatic α-cells limit Ca2+ entry and glucagon secretion by maintaining membrane hyperpolarization; inhibition (A1899) or genetic ablation of α-cell TASK-1 increases electrical excitability and Ca2+ influx under high glucose, elevating glucagon secretion. Mice with α-cell-specific TASK-1 deletion show improved glucose inhibition of glucagon secretion. Patch-clamp electrophysiology in human and mouse α-cells, α-cell-specific conditional TASK-1 knockout mice, Ca2+ imaging, glucagon secretion assays, TASK-1 inhibitor A1899 Molecular endocrinology (Baltimore, Md.) High 25849724
2015 In human atrial cardiomyocytes, single-channel recordings reveal a ~55-pS channel consistent with TASK-1/TASK-3 heteromers; co-expression and tandem-construct experiments in HEK293 cells and Xenopus oocytes confirm that TASK-1/TASK-3 heteromers have a predominant surface expression and reduced affinity for TASK-1-selective blockers compared with homomers. Cell-attached single-channel patch-clamp of human right auricle cardiomyocytes, TASK-1/TASK-3 tandem constructs and co-expression in HEK293/oocytes, immunocytochemistry Journal of molecular and cellular cardiology Medium 25655935
2019 Sp1 transcription factor upregulates p11 (S100A10) expression, which in turn reduces functional TASK-1 expression at the plasma membrane, increasing neuronal excitability. In the SOD1-G93A ALS mouse model, Sp1-p11-TASK1 dysregulation contributes to motor neuron hyperexcitability and degeneration; knockdown of either Sp1 or p11 is neuroprotective. Sp1 and p11 siRNA/overexpression, SOD1-G93A mouse model, patch-clamp recordings, immunofluorescence of channel surface expression, nitrosative stress stimulation of Sp1 promoter Nature communications Medium 31439839
2020 X-ray crystal structure of TASK-1 reveals a lower 'X-gate' formed by the crossed C-terminal M4 helices (residues 243VLRFMT248); this gate controls channel open probability and responds to volatile anesthetics and GPCR signals. X-gate mutations alter open probability and anesthetic response. Two high-affinity inhibitors bind below the selectivity filter and are trapped in the vestibule by the closed X-gate, explaining their exceptionally slow washout. X-ray crystallography of TASK-1 alone and in complex with two inhibitors, site-directed mutagenesis of X-gate residues, electrophysiological functional validation Nature High 32499642
2022 De novo gain-of-function mutations in KCNK3 cluster around the X-gate and produce constitutively overactive TASK-1 channels that no longer respond to inhibition by G-protein-coupled receptor pathways, causing a developmental disorder with sleep apnea (DDSA). Despite defective X-gating, these channels remain sensitive to pharmacological TASK channel inhibitors. Patch-clamp electrophysiology of mutant TASK-1 in heterologous cells, GPCR pathway modulation assays, pharmacological inhibitor screening, clinical genetics Nature genetics High 36195757
2014 TASK-1 current in atrial myocytes from humans and canines with chronic atrial fibrillation is absent despite unchanged or slightly increased total TASK-1 protein; addition of phosphatase to the patch pipette restores TASK-1 current, indicating that phosphorylation-dependent inhibition (not downregulation of protein) accounts for loss of current in chronic AF. Patch-clamp of isolated human and canine atrial myocytes, intrapipette phosphatase application, Western blot of total TASK-1 protein American journal of physiology. Heart and circulatory physiology Medium 25437921
2015 TASK-1 knockdown in the NSCLC cell line A549 (which expresses functional, pH- and hypoxia-sensitive TASK-1 currents) significantly enhances apoptosis and reduces proliferation; this effect is absent in weakly expressing NCI-H358 cells, indicating a cell-context-dependent role for TASK-1 in cancer cell survival. siRNA knockdown, patch-clamp electrophysiology in A549 cells, apoptosis and proliferation assays PloS one Medium 27294516
2012 Reactive oxygen species (H2O2 at millimolar concentrations applied intracellularly) activate TASK-1, TASK-3, and TASK-1/TASK-3 heteromers in inside-out patches, but extracellular or superoxide-generating ROS do not inhibit TASK channels; thus ROS are unlikely to be the hypoxic signal mediating TASK inhibition in chemoreceptor cells. Inside-out, cell-attached, and outside-out patch-clamp in HeLa cells, carotid body glomus cells, adrenal cells, and cerebellar granule neurons; xanthine/XO superoxide generation; DTT and MTSEA treatment Pflugers Archiv : European journal of physiology Medium 23007462
2015 TASK-1 K+ channel modulates β-adrenergic thermogenic response in brown adipocytes; Task1-null mice develop BAT whitening and impaired β3-adrenergic response (decreased O2 consumption, UCP1 expression, lipolysis). This phenotype is mediated by exacerbated mineralocorticoid receptor (MR) signaling, as it is mimicked by corticoids and reversed by an MR inhibitor. Task1 knockout mice, brown adipocyte isolation and differentiation, oxygen consumption assays, MR pharmacological inhibition/corticoid stimulation, Ucp1 expression measurements FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 26527067
2019 Doxapram inhibits human TASK-1 and TASK-3 channels equipotently; mutations of hydrophobic residues in the pore-lining region or removal of the TASK-3 C-terminus attenuate doxapram inhibition but not zinc block, indicating an intracellular/pore-lining binding site distinct from the extracellular zinc site. The positive enantiomer GAL-054 is more potent than doxapram; the negative enantiomer GAL-053 has little effect. Whole-cell patch-clamp in tsA201 cells, site-directed mutagenesis of pore-lining residues, C-terminus deletion constructs, chirally separated enantiomers Acta physiologica (Oxford, England) Medium 31423744
2018 PAH-associated TASK-1 missense mutations G106R and L214R reduce channel current markedly despite normal plasma membrane localization (confirmed by confocal microscopy and in-cell/on-cell westerns); WT TASK-1 is activated by riociguat (guanylate cyclase activator), but neither pH 8.4, ONO-RS-082, nor riociguat restores current through these mutant channels. Whole-cell patch-clamp in tsA201 cells, confocal microscopy, in-cell and on-cell western quantification The Journal of physiology Medium 30365877

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2006 Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circulation research 182 16574908
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
2010 A complex task? Direct modulation of transcription factors with small molecules. Current opinion in chemical biology 166 20395165
2016 Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension. Circulation 158 26912814
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
2004 Mutual functional destruction of HIV-1 Vpu and host TASK-1 channel. Molecular cell 123 15099524
1998 Aneuploidy: a report of an ECETOC task force. Mutation research 118 9587424
2005 Task-specific expression of the foraging gene in harvester ants. Molecular ecology 111 15723672
2004 Functional expression of TASK-1/TASK-3 heteromers in cerebellar granule cells. The Journal of physiology 108 14678492
2018 A task-invariant cognitive reserve network. NeuroImage 94 29772378
2001 Inhibition of TASK-1 potassium channel by phospholipase C. American journal of physiology. Cell physiology 93 11443069
2008 TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions. The Journal of biological chemistry 90 18375952
2017 Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy. European heart journal 88 28057773
2009 TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system. Brain : a journal of neurology 84 19570851
2015 TASK channels in arterial chemoreceptors and their role in oxygen and acid sensing. Pflugers Archiv : European journal of physiology 83 25623783
2019 Characterization of Kcnk3-Mutated Rat, a Novel Model of Pulmonary Hypertension. Circulation research 80 31347976
2020 A lower X-gate in TASK channels traps inhibitors within the vestibule. Nature 72 32499642
2018 Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension. Cardiovascular research 64 29360952
2007 The TASK background K2P channels: chemo- and nutrient sensors. Trends in neurosciences 64 17945357
2017 TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications. The European respiratory journal 62 29122916
2010 From the background to the spotlight: TASK channels in pathological conditions. Brain pathology (Zurich, Switzerland) 62 20529081
2023 Explainable multi-task learning for multi-modality biological data analysis. Nature communications 58 37137905
2004 Photochemical genotoxicity: principles and test methods. Report of a GUM task force. Mutation research 58 14706512
2015 MicroRNA-mediated regulation of p21 and TASK1 cellular restriction factors enhances HIV-1 infection. Journal of cell science 57 25717002
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
2016 An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension. Clinical genetics 52 27649371
2009 Endothelin-1 inhibits background two-pore domain channel TASK-1 in primary human pulmonary artery smooth muscle cells. American journal of respiratory cell and molecular biology 50 19188660
2009 The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone. Naunyn-Schmiedeberg's archives of pharmacology 49 19777211
2002 TASK-1, TASK-2, TASK-3 and TRAAK immunoreactivities in the rat carotid body. Brain research 49 12231257
2019 RNA editing is abundant and correlates with task performance in a social bumblebee. Nature communications 48 30962428
2002 Expression of TASK-1, a pH-sensitive twin-pore domain K(+) channel, in rat myocytes. American journal of physiology. Heart and circulatory physiology 47 12063289
2013 A daunting task: manipulating leukocyte function with RNAi. Immunological reviews 46 23550647
2008 The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice. Neurobiology of disease 46 18930826
2012 TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation. British journal of pharmacology 45 21838752
2011 Relationship of DAT1 and adult ADHD to task-positive and task-negative working memory networks. Psychiatry research 44 21596533
2011 Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels. British journal of pharmacology 42 21410455
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
2018 MODE-TASK: large-scale protein motion tools. Bioinformatics (Oxford, England) 41 29850770
2016 TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers. PloS one 41 27294516
2009 The role of TASK1 in aldosterone production and its expression in normal adrenal and aldosterone-producing adenomas. Clinical endocrinology 41 19878209
2014 Cloning, functional characterization, and remodeling of K2P3.1 (TASK-1) potassium channels in a porcine model of atrial fibrillation and heart failure. Heart rhythm 40 24952150
2014 Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. Bioorganic & medicinal chemistry letters 40 25017033
2021 MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics. Computational and structural biotechnology journal 38 34589183
2018 Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension. The Journal of physiology 37 30365877
2007 Dorsal and ventral processing under dual-task conditions. Psychological science 37 17425526
2015 TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes. Journal of molecular and cellular cardiology 36 25655935
2013 A gutsy task: generating intestinal tissue from human pluripotent stem cells. Digestive diseases and sciences 36 23532718
2012 The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis. Experimental neurology 36 22960185
2015 TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion. Molecular endocrinology (Baltimore, Md.) 35 25849724
2013 The task force that rescues stalled ribosomes in bacteria. Trends in biochemical sciences 35 23820510
2015 The K+ channel TASK1 modulates β-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 26527067
2021 Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload. Cardiovascular research 32 33483721
2016 A dual phosphorylation switch controls 14-3-3-dependent cell surface expression of TASK-1. Journal of cell science 32 26743085
2007 Forward Transport of K2p3.1: mediation by 14-3-3 and COPI, modulation by p11. Traffic (Copenhagen, Denmark) 32 17908283
2022 MicroRNAs Regulate TASK-1 and Are Linked to Myocardial Dilatation in Atrial Fibrillation. Journal of the American Heart Association 30 35301863
2020 In vivo miR-138-5p inhibition alleviates monocrotaline-induced pulmonary hypertension and normalizes pulmonary KCNK3 and SLC45A3 expression. Respiratory research 30 32678044
2017 The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery. Journal of the American Heart Association 30 28889099
2016 KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension. Hypertension (Dallas, Tex. : 1979) 30 27296998
2016 Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension. Revista espanola de cardiologia (English ed.) 29 27453251
2023 Combatting persister cells: The daunting task in post-antibiotics era. Cell insight 28 37304393
2021 Modeling multi-species RNA modification through multi-task curriculum learning. Nucleic acids research 27 33744973
2010 Expression of the kcnk3 potassium channel gene lessens the injury from cerebral ischemia, most likely by a general influence on blood pressure. Neuroscience 26 20167264
2020 Vitamin D deficiency downregulates TASK-1 channels and induces pulmonary vascular dysfunction. American journal of physiology. Lung cellular and molecular physiology 25 32726132
2020 Down-regulation of lncRNA Gas5 promotes hypoxia-induced pulmonary arterial smooth muscle cell proliferation by regulating KCNK3 expression. European journal of pharmacology 25 33010302
2019 Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1. Nature communications 25 31439839
2004 Developmental expression of two-pore domain K+ channels, TASK-1 and TREK-1, in the rat cochlea. Neuroreport 24 15094499
2022 KCNK3 inhibits proliferation and glucose metabolism of lung adenocarcinoma via activation of AMPK-TXNIP pathway. Cell death discovery 23 35963847
2022 Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea. Nature genetics 23 36195757
2024 Hemoadsorption therapy for myoglobin removal in rhabdomyolysis: consensus of the hemoadsorption in rhabdomyolysis task force. BMC nephrology 22 39085790
2014 Task relevance regulates the interaction between reward expectation and emotion. Experimental brain research 21 24553754
2012 N-glycosylation-dependent control of functional expression of background potassium channels K2P3.1 and K2P9.1. The Journal of biological chemistry 21 23250752
2021 Task-induced modulations of neuronal activity along the auditory pathway. Cell reports 20 34910908
2014 KCNK3: new gene target for pulmonary hypertension? Expert review of respiratory medicine 20 24742047
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
2004 Postnatal changes in TASK-1 and TREK-1 expression in rat brain stem and cerebellum. Neuroreport 20 15167558
2021 Rodent mnemonic similarity task performance requires the prefrontal cortex. Hippocampus 19 33606338
2021 Current Drug Treatment Strategies for Atrial Fibrillation and TASK-1 Inhibition as an Emerging Novel Therapy Option. Frontiers in pharmacology 19 33897427
2020 Timing of response onset and offset in macaque V4: stimulus and task dependence. Journal of neurophysiology 19 32401171
2020 Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells. International journal of molecular sciences 19 33036472
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
2016 Controlling DNA-End Resection: An Emerging Task for Ubiquitin and SUMO. Frontiers in genetics 19 27602047
2013 TASK-1 channels in oligodendrocytes: a role in ischemia mediated disruption. Neurobiology of disease 19 23567653
2019 TASK Channels Pharmacology: New Challenges in Drug Design. Journal of medicinal chemistry 18 31260312
2014 Cooperative endocytosis of the endosomal SNARE protein syntaxin-8 and the potassium channel TASK-1. Molecular biology of the cell 18 24743596
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
2023 Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart. The Journal of physiology 17 37477289
2021 KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models. International journal of molecular sciences 17 34065088
2020 Inhibition of RELM-β prevents hypoxia-induced overproliferation of human pulmonary artery smooth muscle cells by reversing PLC-mediated KCNK3 decline. Life sciences 17 32045592
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
2010 Protein kinase G dynamically modulates TASK1-mediated leak K+ currents in cholinergic neurons of the basal forebrain. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 20410120
2024 Role of KCNK3 Dysfunction in Dasatinib-associated Pulmonary Arterial Hypertension and Endothelial Cell Dysfunction. American journal of respiratory cell and molecular biology 16 38546978
2016 pH-dependent inhibition of K₂P3.1 prolongs atrial refractoriness in whole hearts. Pflugers Archiv : European journal of physiology 16 26729267
2014 TASK-1 current is inhibited by phosphorylation during human and canine chronic atrial fibrillation. American journal of physiology. Heart and circulatory physiology 16 25437921
2012 BioNLP Shared Task--The Bacteria Track. BMC bioinformatics 16 22759457
2012 The acid-sensitive, anesthetic-activated potassium leak channel, KCNK3, is regulated by 14-3-3β-dependent, protein kinase C (PKC)-mediated endocytic trafficking. The Journal of biological chemistry 16 22846993
2004 Selectivity and interactions of Ba2+ and Cs+ with wild-type and mutant TASK1 K+ channels expressed in Xenopus oocytes. The Journal of physiology 16 15611021
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

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