Affinage

KCNK2

Potassium channel subfamily K member 2 · UniProt O95069

Length
426 aa
Mass
47.1 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 35 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

KCNK2 (TREK-1) is a polymodally gated two-pore-domain background K+ channel that sets resting membrane potential and integrates physical and chemical stimuli into changes in K+ conductance (PMID:11319556, PMID:23897808). The channel is intrinsically mechanosensitive: purified TREK-1 reconstituted in liposomes is gated directly by membrane bilayer tension without accessory proteins, and its selectivity filter participates in both ion selectivity and stretch-induced gating/desensitization (PMID:23897808, PMID:28242754). It is also activated by heat (PMID:10835347), lysophospholipids acting through its C-terminus (PMID:10744694), and membrane phospholipids including PIP2, with a C-terminal positively charged cluster serving as the phospholipid-sensing domain and the proton sensor E306 mediating activation by intracellular acidosis (PMID:15577940). External acidification conversely closes the channel through C-type gating governed by external-loop histidines (PMID:18474599). TREK-1 gating is reversibly tuned by phosphorylation, interconverting leak and voltage-dependent behaviors (PMID:11319556): PKA phosphorylation of Ser333 enables sequential phosphorylation at Ser300 to inhibit the channel downstream of Gq/PKC signaling, while PKG phosphorylation at Ser351 activates it via the NO/cGMP pathway (PMID:16006563, PMID:11560940). Channel surface expression and assembly are controlled by partners and isoforms — βIV-spectrin targets TREK-1 to cardiomyocyte membranes (PMID:24445605), a disulfide-linked TWIK-1/TREK-1 heterodimer forms in astrocytes (PMID:24496152), TREK-1/TREK-2 heterodimers arise in sensory neurons (PMID:27129242), and N-terminally truncated or pore-deficient splice variants are ER-retained and suppress surface expression of full-length channel (PMID:24196565). Functionally, TREK-1 is essential in vivo for PUFA-mediated neuroprotection and volatile anesthetic action (PMID:15175651), polymodal heat/cold/mechanical pain sensing (PMID:16675954, PMID:19279663), morphine analgesia (PMID:24346231), serotonin-dependent mood regulation (PMID:16906152), hippocampal excitability, LTP, and memory (PMID:31728930), and cardiac sinoatrial excitability (PMID:27098968). In astrocytes, Gi-coupled GPCR activation releases Gβγ, which binds the TREK-1 N-terminus to drive fast non-vesicular glutamate release (PMID:23021213, PMID:30319359).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2000 High

    Establishing that TREK-1 is a thermosensitive channel under cAMP/PKA control answered how a background K+ channel could couple temperature to neuronal signaling and be switched off by GPCR signaling.

    Evidence Patch-clamp with Ser333 mutagenesis in heterologous cells

    PMID:10835347

    Open questions at the time
    • Did not resolve how thermal energy is transduced to the gate
    • Physiological temperature range relevance untested in vivo at this stage
  2. 2000 High

    Domain mapping of lysophospholipid and riluzole responses localized lipid-sensing to the C-terminus and confirmed PKA phosphorylation as a dominant inhibitory switch.

    Evidence Cell-attached vs excised patch recording, C-terminal deletions, and PKA-site mutagenesis

    PMID:10744694 PMID:10779373

    Open questions at the time
    • Identity of the cytosolic factor required for LPC activation not defined
    • Did not establish direct vs indirect lipid binding
  3. 2001 High

    Demonstrating reversible phosphorylation-driven interconversion between leak and voltage-dependent gating reframed TREK-1 as a dynamically regulated channel rather than a static background conductance.

    Evidence Single-channel recording of native hippocampal and cloned channels

    PMID:11319556

    Open questions at the time
    • Kinase/phosphatase set governing interconversion in native cells not fully mapped
  4. 2001 High

    Identification of the PKG site Ser351 showed that NO/cGMP signaling activates TREK-1 independently of the inhibitory PKA pathway, establishing antagonistic phospho-regulation.

    Evidence Patch-clamp in COS cells with Ser351 mutagenesis and cGMP donors

    PMID:11560940

    Open questions at the time
    • In vivo settings where PKG regulation dominates not defined
  5. 2004 High

    Mapping the C-terminal phospholipid-sensing cluster and proton sensor E306 unified lipid, pressure, and pH gating into a single membrane-interaction mechanism.

    Evidence Patch-clamp with E306 and charged-cluster mutagenesis

    PMID:15577940

    Open questions at the time
    • Structural geometry of C-terminus/membrane interaction not solved
    • Did not separate PIP2 from other phospholipid contributions quantitatively
  6. 2004 High

    Knockout mice established that TREK-1 is physiologically required for PUFA neuroprotection and volatile anesthetic action, moving the channel from in vitro pharmacology to validated in vivo target.

    Evidence Trek1-/- mice in ischemia, epilepsy, and anesthesia paradigms

    PMID:15175651

    Open questions at the time
    • Cell types mediating each phenotype not dissected
    • Compensation by other K2P channels not excluded
  7. 2005 High

    The sequential PKA-then-PKC phosphorylation model explained how Gq-coupled receptors inhibit TREK-1 through coordinated Ser333/Ser300 modification.

    Evidence Patch-clamp in HEK293 with combinatorial S300/S333 mutagenesis and kinase inhibitors

    PMID:16006563

    Open questions at the time
    • Order and stoichiometry of phosphorylation in native cells not directly measured
  8. 2005 High

    Linking E306 and the N-terminus to antidepressant block, and showing TREK-1 reshapes the actin cytoskeleton, connected the channel's chemical sensors to drug action and cell morphology.

    Evidence Patch-clamp with E306A/truncation mutants (fluoxetine) and live-cell imaging of cytoskeletal protrusions

    PMID:15685212 PMID:15976821 PMID:21740918

    Open questions at the time
    • Mechanism by which a K+ channel remodels actin independent of permeation unresolved
    • Direct fluoxetine binding site not structurally defined
  9. 2006 High

    Behavioral knockout studies established TREK-1 as a regulator of serotonergic mood signaling and of polymodal pain thresholds, defining its CNS and sensory roles.

    Evidence Trek1-/- mice in depression models and single-fiber/behavioral pain assays

    PMID:16675954 PMID:16906152

    Open questions at the time
    • Circuit-level mechanism linking TREK-1 loss to 5-HT efficacy not mapped
    • Neuronal populations driving pain phenotypes not isolated
  10. 2008 High

    Resolving external pH gating via His87/His141 and Glu84 defined a selectivity-filter (C-type) gate distinct from the intracellular proton sensor, giving TREK-1 bidirectional pH control.

    Evidence Patch-clamp with external-loop and filter mutagenesis plus ion selectivity measurements

    PMID:18474599

    Open questions at the time
    • Structural coupling between external protonation and filter collapse inferred, not directly visualized
  11. 2009 High

    Dual TREK-1/TRAAK knockout work extended mechanosensitive K2P channels to cold pain thresholds, broadening TREK-1's thermosensory range.

    Evidence Trek1/Traak knockout mice with behavioral and single-fiber recordings

    PMID:19279663

    Open questions at the time
    • Relative contribution of TREK-1 vs TRAAK to cold sensing not separated
  12. 2012 High

    Discovery that Gβγ binds the TREK-1 N-terminus to open the channel revealed a non-vesicular glutamate release mechanism downstream of Gi-coupled GPCRs in astrocytes.

    Evidence Reciprocal Co-IP, sniffer-patch glutamate detection, immunoEM, and shRNA in astrocytes

    PMID:23021213

    Open questions at the time
    • Structural basis of Gβγ/N-terminus interaction not solved
    • How K+ channel opening produces glutamate efflux mechanistically unresolved
  13. 2013 High

    Reconstitution of purified TREK-1 in liposomes proved intrinsic mechanosensitivity, settling whether tension gating requires accessory proteins.

    Evidence Purified channel reconstituted in giant liposomes with patch-clamp under pressure

    PMID:23897808

    Open questions at the time
    • Conformational changes linking tension to gate not directly imaged
  14. 2013 High

    Mapping morphine analgesia to TREK-1 while sparing constipation, respiratory depression, and dependence identified the channel as a route to dissociate opioid benefit from harm.

    Evidence Trek1-/- mice across analgesic and adverse-effect assays

    PMID:24346231

    Open questions at the time
    • Neuronal circuit coupling MOR to TREK-1 in analgesia not defined
  15. 2014 High

    Identifying βIV-spectrin as a targeting partner and the disulfide-linked TWIK-1/TREK-1 heterodimer established that TREK-1 surface delivery and channel composition are partner-dependent in cardiomyocytes and astrocytes.

    Evidence Co-IP, Cys mutagenesis, qv4J mouse electrophysiology, and gene silencing

    PMID:24445605 PMID:24496152

    Open questions at the time
    • Trafficking machinery downstream of βIV-spectrin not detailed
    • Stoichiometry of heterodimer vs homodimer pools in vivo unknown
  16. 2016 High

    Cardiac conditional knockouts and the βIV-spectrin axis established TREK-1's role in sinoatrial node excitability and rhythm.

    Evidence Cardiomyocyte-specific Kcnk2 deletion and qv4J mice with SAN electrophysiology and localization imaging

    PMID:27098968

    Open questions at the time
    • Quantitative contribution of TREK-1 current to pacemaker potential not isolated
  17. 2016 High

    Demonstrating functional TREK-1/TREK-2 heterodimers in DRG neurons showed that native K2P pharmacology and biophysics arise from mixed-subunit channels.

    Evidence Tandem constructs, Co-IP, and ruthenium red pharmacology in oocytes and DRG neurons

    PMID:27129242

    Open questions at the time
    • Physiological prevalence of heterodimers across tissues not quantified
  18. 2017 High

    A disease-associated selectivity-filter mutation conferring Na+ permeability and stretch hypersensitivity linked TREK-1 mechanogating defects to ventricular tachycardia.

    Evidence Patch-clamp of mutant channel, selectivity and stretch assays, and cardiac modeling

    PMID:28242754

    Open questions at the time
    • Single-patient genetic context; broader causal validation in families not described in corpus
  19. 2018 High

    Cell-type-specific knockouts revealed a fibroblast-autonomous, JNK-linked role for TREK-1 in pressure-overload cardiac fibrosis, distinct from its cardiomyocyte functions.

    Evidence Fibroblast- vs cardiomyocyte-specific conditional knockout in pressure overload with JNK and fibrosis readouts

    PMID:30153110

    Open questions at the time
    • How TREK-1 conductance couples to JNK activation in fibroblasts not mechanistically defined
  20. 2019 High

    Hippocampal knockout analysis tied TREK-1 loss to altered spine morphology, synaptic transmission, occluded LTP, and memory deficits, defining its cognitive role.

    Evidence Trek1 knockout mice with patch-clamp, LTP recordings, spine morphology, and behavioral memory testing

    PMID:31728930

    Open questions at the time
    • Whether synaptic changes are cell-autonomous or network adaptations not separated
  21. 2019 Medium

    A PLD2/phosphatidic acid model proposed that palmitate-mediated localization generates local lipid second messengers gating TREK-1, offering a shared route for mechanical and anesthetic activation.

    Evidence Lipid biochemistry and membrane localization with PA gating assays

    PMID:31672538

    Open questions at the time
    • Full reconstitution and mutagenesis evidence not described
    • Single-lab model awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TREK-1's distinct sensors (tension, lipids, protons, phosphorylation, Gβγ) converge on a unified gate, and how its K+ conductance mechanistically drives downstream events like astrocytic glutamate release and fibroblast JNK activation, remain unresolved.
  • No integrated structural model of multimodal gating in the corpus
  • Causal link between K+ flux and non-canonical signaling outputs unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0008289 lipid binding 3 GO:0140299 molecular sensor activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005856 cytoskeleton 1
Partners
COCHGNB1KCNK10KCNK6OPRM1SPTBN4
Complex memberships
TREK-1/TREK-2 heterodimerTWIK-1/TREK-1 heterodimerbeta-IV-spectrin/TREK-1 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TREK-1 is directly activated by heat in a reversible manner; a 10°C rise enhances current ~7-fold. Prostaglandin E2 and cAMP reverse thermal opening via PKA-mediated phosphorylation of Ser333. Patch-clamp electrophysiology, site-directed mutagenesis (Ser333) The EMBO journal High 10835347
2000 Lysophospholipids (e.g., lysophosphatidylcholine) activate TREK-1 in cell-attached patches but not excised patches, indicating indirect activation requiring a cytosolic factor; the carboxyl-terminal region of TREK-1 (not the amino terminus or extracellular M1P1 loop) is critically required for LPC activation. Patch-clamp electrophysiology (cell-attached and excised patches), C-terminal deletion mutagenesis The Journal of biological chemistry High 10744694
2000 Riluzole transiently activates TREK-1 followed by inhibition; the inhibitory phase is due to riluzole-induced increase in intracellular cAMP leading to PKA-dependent phosphorylation. TREK-1 mutants lacking the PKA phosphorylation serine residue are activated in a sustained manner by riluzole. Whole-cell patch-clamp, site-directed mutagenesis of PKA phosphorylation site Molecular pharmacology High 10779373
2001 Phosphorylation of native hippocampal and cloned KCNK2 channels produces reversible interconversion between leak (background) and voltage-dependent phenotypes, demonstrating dynamic regulation of channel gating by phosphorylation. Single-channel patch-clamp recording of native hippocampal and recombinant KCNK2 channels Nature neuroscience High 11319556
2001 TREK-1 is regulated by NO/cGMP pathway: sodium nitroprusside and 8-Br-cGMP increase TREK-1 currents, and mutation of the PKG consensus site at serine 351 abolishes this stimulatory effect without affecting PKA-mediated inhibition. Whole-cell and single-channel patch-clamp in COS cells expressing TREK-1, site-directed mutagenesis (Ser351) The Journal of biological chemistry High 11560940
2004 Membrane phospholipids including PIP2 control TREK-1 gating; a positively charged cluster in the C-terminal domain is the phospholipid-sensing domain that interacts with the plasma membrane. Proton sensor E306 in this region is required for activation by cytosolic acidosis; protonation of E306 tightens channel-phospholipid interaction and opens TREK-1 at atmospheric pressure. Patch-clamp electrophysiology, site-directed mutagenesis (E306 and C-terminal charged cluster) The EMBO journal High 15577940
2004 TREK-1 knockout mice show increased sensitivity to ischemia and epilepsy; neuroprotection by polyunsaturated fatty acids (PUFAs) is abolished in Trek1−/− mice, establishing TREK-1 as essential for PUFA-mediated neuroprotection. Genetic knockout mouse model, ischemia and epilepsy models in vivo The EMBO journal High 15175651
2004 Trek1−/− mice are resistant to volatile anesthetic-induced anesthesia, establishing TREK-1 as a functional target of volatile anesthetics in vivo. Genetic knockout mouse model, anesthesia sensitivity testing The EMBO journal High 15175651
2005 Activation of Gαq-coupled receptors (thyrotropin-releasing hormone receptor, Orexin receptor) inhibits TREK-1 via PKC. A sequential phosphorylation model was established: PKA phosphorylates Ser333, which enables subsequent phosphorylation at Ser300, together inhibiting channel activity. S333A and S300A mutations enhance basal current; S333D and S300D mimick phosphorylation and reduce currents. Whole-cell patch-clamp in HEK293 cells, pharmacological PKC/PKA inhibitors, systematic mutagenesis of Ser300 and Ser333 The Journal of biological chemistry High 16006563
2005 Fluoxetine and norfluoxetine inhibit human TREK-1 (IC50 19 μM and 9 μM, respectively) in a voltage-independent manner. The E306A mutation reduces fluoxetine inhibition (~40% block vs. 84%), linking the intracellular proton sensor to drug sensitivity. C-terminal truncation does not affect fluoxetine block. Whole-cell patch-clamp in tsA201 cells, systematic C-terminal truncation and E306A mutagenesis British journal of pharmacology High 15685212
2005 TREK-1 expression markedly alters the cytoskeletal network and induces formation of actin- and ezrin-rich membrane protrusions. Cytoskeletal remodeling requires the PKA phosphorylation site S333 and proton sensor E306 but is independent of channel permeation. Conversely, the actin cytoskeleton tonically represses TREK-1 mechanosensitivity. Live-cell imaging, fluorescence microscopy, mutagenesis (S333, E306), genetic inactivation of TREK-1 in striatal neurons EMBO reports High 15976821
2006 Deletion of TREK-1 (Kcnk2−/−) in mice leads to increased efficacy of serotonin (5-HT) neurotransmission and resistance to depression in five behavioral models, with reduced stress-induced corticosterone elevation, establishing TREK-1 as a regulator of 5-HT signaling and mood. Genetic knockout mouse model, five depression behavioral models, neurochemical (corticosterone) measurements Nature neuroscience High 16906152
2006 Trek1−/− mice display increased sensitivity to painful heat near the noxious threshold, increased sensitivity to low-threshold mechanical stimuli, and increased thermal/mechanical hyperalgesia under inflammation. Polymodal C-fibers in KO mice are more heat sensitive, establishing TREK-1 as a molecular sensor for polymodal pain. Genetic knockout mouse model, single-fiber recordings, behavioral pain assays, inflammation models The EMBO journal High 16675954
2008 External acidification inhibits human K2P2.1 (TREK-1) by inducing C-type gating closure. Histidine residues His87 and His141 in the first external loop govern this pH response; protonation generates local positive charge that draws Glu84 away from its interactions, collapsing the selectivity filter. Mutation S164Y accelerates C-type gating. Whole-cell patch-clamp, site-directed mutagenesis of His87, His141, Glu84, S164Y; ion selectivity measurements The Journal of biological chemistry High 18474599
2009 TRAAK and TREK-1 channels (mechano-gated K+ channels) control both heat and cold pain thresholds in mice. TREK-1 and TRAAK together regulate nociceptor activation by cold, particularly in menthol-insensitive neurons. Genetic knockout mice for TREK-1 and TRAAK, behavioral thermal and mechanical pain assays, single-fiber recordings The EMBO journal High 19279663
2012 TREK-1 mediates fast, nonvesicular glutamate release from astrocytes upon GPCR activation. The mechanism requires Gαi activation, dissociation of Gβγ, and direct interaction of Gβγ with the N-terminus of TREK-1 to open the channel. TREK-1 is preferentially localized at astrocyte cell body and processes (not microdomains near synapses). Co-immunoprecipitation (Gβγ–TREK-1 N-terminus interaction), sniffer-patch glutamate detection, immunoelectron microscopy, shRNA knockdown, GPCR pharmacology Cell High 23021213
2013 Purified mouse TREK-1 reconstituted in giant liposomes is directly sensitive to membrane tension: intrinsic lipid bilayer tension is sufficient to maximally activate the channel, and positive pressure closes it. This demonstrates TREK-1 is an intrinsically mechanosensitive channel requiring no accessory proteins. Protein purification from yeast, reconstitution in giant liposomes, patch-clamp electrophysiology The Journal of biological chemistry High 23897808
2013 TREK-1 mediates morphine-induced analgesia downstream of μ-opioid receptor signaling in mice, but is not involved in morphine-induced constipation, respiratory depression, or dependence, separating analgesic from adverse opioid effects. Genetic knockout mouse model (Trek1−/−), behavioral pain assays, opioid adverse-effect assays Nature communications High 24346231
2014 Native TWIK-1 and TREK-1 form a functional heterodimeric channel in astrocytes via a disulfide bridge between TWIK-1 Cys69 and TREK-1 Cys93. Surface expression of TWIK-1 and TREK-1 are interdependent. The TWIK-1/TREK-1 heterodimer mediates astrocytic passive conductance and cannabinoid-induced glutamate release. Co-immunoprecipitation, site-directed mutagenesis of Cys69/Cys93, gene silencing, patch-clamp electrophysiology, glutamate release assays Nature communications High 24496152
2014 βIV-spectrin, an actin-associated protein, colocalizes with TREK-1 at the myocyte intercalated disc, physically associates with TREK-1, and is required for TREK-1 membrane targeting. Mice expressing βIV-spectrin lacking TREK-1 binding (qv4J) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia. Co-immunoprecipitation, immunofluorescence colocalization, functional electrophysiology in qv4J mice, action potential recordings Cardiovascular research High 24445605
2016 βIV-spectrin/TREK-1 complex is required for normal sinoatrial node cell excitability. Cardiomyocyte-specific deletion of TREK-1 causes sinoatrial dysfunction with bradycardia and sinus pauses under stress. Loss of βIV-spectrin (qv4J mice) disrupts normal TREK-1 membrane localization in sinoatrial cells. Cardiac-specific conditional knockout mice (αMHC-Kcnk2f/f), action potential measurements, sinoatrial node cell electrophysiology, TREK-1 localization imaging Journal of the American Heart Association High 27098968
2016 TREK-1 and TREK-2 subunits form functional heterodimers in heterologous expression and in native dorsal root ganglion neurons. The TREK-1/TREK-2 heterodimer has unique biophysical and pharmacological properties (single-channel conductance intermediate between homodimers; ruthenium red sensitivity intermediate between TREK-1 and TREK-2). Assembly confirmed by co-immunoprecipitation. Tandem-construct expression, co-immunoprecipitation of epitope-tagged subunits in Xenopus oocytes, patch-clamp electrophysiology, ruthenium red pharmacology in DRG neurons The Journal of biological chemistry High 27129242
2017 A heterozygous point mutation in the selectivity filter of TREK-1 introduces abnormal sodium permeability and hypersensitivity to stretch-activation, associated with ventricular tachycardia. This indicates the selectivity filter is directly involved in stretch-induced activation and desensitization. Patch-clamp electrophysiology of mutant TREK-1, ion selectivity measurements, stretch-activation assays, computational cardiac modeling EMBO molecular medicine High 28242754
2018 Cardiac fibroblast-specific (not cardiomyocyte-specific) TREK-1 deletion prevents pressure overload-induced cardiac dysfunction. Loss of TREK-1 in fibroblasts is associated with diminished cardiac fibrosis and reduced JNK activation in both cardiomyocytes and fibroblasts. Cell-type-specific conditional knockout mice, pressure overload model, cardiac function assessment, JNK signaling analysis, fibrosis measurements The Journal of clinical investigation High 30153110
2019 Phospholipase D2 (PLD2) localizes to TREK-1 through palmitate-mediated lipid compartmentalization and generates local high concentrations of phosphatidic acid (PA) that gates TREK-1. Disruption of palmitate-mediated PLD2 localization is proposed as a shared pathway for both mechanical force and anesthetic activation of TREK-1. Lipid biochemistry, membrane localization experiments, channel gating assays with PA Biochimica et biophysica acta. Biomembranes Medium 31672538
2013 TREK-1 splice variant TREK-1e (lacking transmembrane domains M3/M4 and second pore domain) is retained in the endoplasmic reticulum and reduces surface expression and current density of full-length TREK-1 when co-expressed. Residues I204 and W205 in the C-terminus of TREK-1e mediate ER retention. Live-cell imaging of GFP-tagged constructs, surface expression assays, mutagenesis of ER retention signal, electrophysiology in Xenopus oocytes, reporter fusion constructs Pflugers Archiv : European journal of physiology High 24196565
2011 TREK-1 alternative translation initiation generates two isoforms; the truncated isoform (TREK-1[ΔN52]) lacking the first 52 amino acids shows reduced K+ selectivity and 70% reduced sensitivity to fluoxetine inhibition, indicating the N-terminal 52 amino acids are essential for fluoxetine sensitivity. Electrophysiology (HEK-293 cells and Xenopus oocytes), alternative translation initiation mutagenesis (TREK-1[M53I], TREK-1[ΔN52]) Neuropharmacology High 21740918
2015 In pituitary corticotropes, arginine vasopressin suppresses background TREK-1 current via PKC activation, causing membrane depolarization. AVP and CRH have additive effects on TREK-1 current suppression via PKC and PKA pathways respectively, resulting in greater depolarization and potentiated ACTH secretion. Perforated patch-clamp in mouse corticotropes, pharmacological PKC inhibition, PKA pathway activation, Ca2+ buffering experiments Endocrinology High 26248219
2018 Activation of astrocytic μ-opioid receptor (MOR) by DAMGO causes fast glutamate release via TREK-1-containing K2P channels. MOR and TREK-1 are co-localized in astrocyte soma and processes. Glutamate release is reduced by TREK-1 gene silencing and absent in MOR-deficient astrocytes. Sniffer-patch glutamate detection, shRNA gene silencing of TREK-1, MOR-deficient mice, immunofluorescence colocalization Frontiers in cellular neuroscience High 30319359
2011 Trek-1 deficiency in alveolar epithelial cells decreases IL-6 secretion via reduced p38 phosphorylation and impaired PKCθ phosphorylation, without affecting Ca2+ signaling. This places TREK-1 upstream of p38 and Ca2+-independent PKC isoforms in the cytokine secretion pathway. shRNA-mediated Trek-1 knockdown in mouse and human AECs, western blot analysis of signaling intermediates (p38, multiple PKC isoforms), ELISA for IL-6, pharmacological inhibition American journal of physiology. Lung cellular and molecular physiology Medium 23275623
2012 TREK-1 activity in astrocytes supports glutamate clearance capacity; suppression of TREK-1 activity inhibits glutamate clearance and enhances astrocyte-derived S100β secretion after ischemic insult, leading to increased neuronal apoptosis. TREK-1 pharmacological inhibition in cultured astrocytes, glutamate uptake assay, S100β ELISA, neuronal apoptosis assay, simulated ischemia model Journal of molecular neuroscience : MN Medium 22895843
2017 Interaction of cochlin (extracellular matrix protein) with TREK-1 in trabecular meshwork cells regulates intraocular pressure. Multimeric cochlin (formed under high shear stress) reduces TREK-1 current, whereas monomeric cochlin does not. TREK-1 silencing in mice prevents cochlin overexpression-mediated IOP increase. Biochemical co-immunoprecipitation/interaction assays, electrophysiology, TREK-1 silencing in mice, IOP measurements Scientific reports Medium 28352076
2019 TREK-1 KO increases dendritic sprouting, immature spine number, neuronal excitability, and both excitatory and inhibitory postsynaptic currents in hippocampal CA1 pyramidal neurons. Increased EPSCs are attributed to increased presynaptic glutamate release probability and enhanced postsynaptic AMPA receptor expression. TREK-1 KO occludes LTP and causes recognition memory deficit. TREK-1 knockout mice, patch-clamp electrophysiology, LTP recordings, morphological analysis of dendritic spines, behavioral memory testing Molecular neurobiology High 31728930
2012 TREK-1 splice variants from preterm labor myometrium interact with full-length wild-type TREK-1; co-immunoprecipitation demonstrates physical interaction. Wild-type TREK-1 is located at the plasma membrane, while splice variants (lacking pore or transmembrane domains) distribute throughout the cell and cause wild-type TREK-1 to redistribute from membrane to cytoplasm when co-expressed. Co-immunoprecipitation of FLAG/His-tagged constructs, subcellular localization imaging in HEK293T cells Biology of reproduction Medium 22811574
2015 Pharmacological differentiation: ruthenium red (RR) inhibits TREK-2 (IC50 = 0.2 μM) but not TREK-1; mutation I110D in TREK-1 (corresponding to D135 in TREK-2 within the extracellular ion pathway) renders TREK-1 sensitive to RR, identifying the extracellular cap residue as the structural determinant of RR sensitivity. Two-electrode voltage clamp (Xenopus oocytes), whole-cell patch clamp (DRG neurons), site-directed mutagenesis (I110D in TREK-1) British journal of pharmacology High 25409575

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 TREK-1, a K+ channel involved in neuroprotection and general anesthesia. The EMBO journal 427 15175651
2000 TREK-1 is a heat-activated background K(+) channel. The EMBO journal 400 10835347
2006 TREK-1, a K+ channel involved in polymodal pain perception. The EMBO journal 334 16675954
2006 Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nature neuroscience 304 16906152
2000 Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. The Journal of biological chemistry 303 10744694
2009 The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. The EMBO journal 300 19279663
2012 TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell 296 23021213
2004 A phospholipid sensor controls mechanogating of the K+ channel TREK-1. The EMBO journal 203 15577940
2000 The neuroprotective agent riluzole activates the two P domain K(+) channels TREK-1 and TRAAK. Molecular pharmacology 196 10779373
2005 Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. British journal of pharmacology 167 15685212
2009 TWIK-1 and TREK-1 are potassium channels contributing significantly to astrocyte passive conductance in rat hippocampal slices. The Journal of neuroscience : the official journal of the Society for Neuroscience 145 19571146
2001 KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nature neuroscience 136 11319556
2001 Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS. Neuroscience 132 11301200
2005 Sequential phosphorylation mediates receptor- and kinase-induced inhibition of TREK-1 background potassium channels. The Journal of biological chemistry 127 16006563
2005 The stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle. Cardiovascular research 126 16248991
2001 TREK-1 regulation by nitric oxide and cGMP-dependent protein kinase. An essential role in smooth muscle inhibitory neurotransmission. The Journal of biological chemistry 122 11560940
2014 A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nature communications 121 24496152
2005 Cross-talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton. EMBO reports 115 15976821
2001 A TREK-1-like potassium channel in atrial cells inhibited by beta-adrenergic stimulation and activated by volatile anesthetics. Circulation research 109 11509450
2007 Polyunsaturated fatty acids are cerebral vasodilators via the TREK-1 potassium channel. Circulation research 97 17556656
2008 A novel mechanism for human K2P2.1 channel gating. Facilitation of C-type gating by protonation of extracellular histidine residues. The Journal of biological chemistry 89 18474599
2008 TREK-1 is a novel molecular target in prostate cancer. Cancer research 87 18281496
2000 Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel. Pflugers Archiv : European journal of physiology 85 10784345
2019 Role of TREK-1 in Health and Disease, Focus on the Central Nervous System. Frontiers in pharmacology 80 31031627
2008 The mechano-gated K(2P) channel TREK-1. European biophysics journal : EBJ 78 18369610
2013 Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nature communications 75 24346231
2018 The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction. The Journal of clinical investigation 71 30153110
2013 The purified mechanosensitive channel TREK-1 is directly sensitive to membrane tension. The Journal of biological chemistry 68 23897808
2002 An ACTH- and ATP-regulated background K+ channel in adrenocortical cells is TREK-1. The Journal of biological chemistry 67 12368289
2017 Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia. EMBO molecular medicine 60 28242754
2018 Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin. Neuropharmacology 57 30056126
2004 Differential expression of the mechanosensitive potassium channel TREK-1 in epicardial and endocardial myocytes in rat ventricle. Experimental physiology 56 15123558
2012 Involvement of TREK-1 activity in astrocyte function and neuroprotection under simulated ischemia conditions. Journal of molecular neuroscience : MN 55 22895843
2003 Expression and localization of TREK-1 K+ channels in human odontoblasts. Journal of dental research 54 12821716
2018 TREK-1 channels regulate pressure sensitivity and calcium signaling in trabecular meshwork cells. The Journal of general physiology 53 30446509
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
2016 Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability. Journal of the American Heart Association 48 27098968
2004 TREK-1 K+ channels couple angiotensin II receptors to membrane depolarization and aldosterone secretion in bovine adrenal glomerulosa cells. American journal of physiology. Endocrinology and metabolism 48 15315905
2004 The lipid-activated two-pore domain K+ channel TREK-1 is resistant to hypoxia: implication for ischaemic neuroprotection. The Journal of physiology 47 15498799
2001 The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K(+) channels TREK-1 and TRAAK. Brain research 47 11172753
2018 Activation of Astrocytic μ-opioid Receptor Elicits Fast Glutamate Release Through TREK-1-Containing K2P Channel in Hippocampal Astrocytes. Frontiers in cellular neuroscience 46 30319359
2013 Expression and effects of modulation of the K2P potassium channels TREK-1 (KCNK2) and TREK-2 (KCNK10) in the normal human ovary and epithelial ovarian cancer. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 43 23479219
2019 Deficiency of TREK-1 potassium channel exacerbates blood-brain barrier damage and neuroinflammation after intracerebral hemorrhage in mice. Journal of neuroinflammation 42 31072336
2014 β(IV)-Spectrin regulates TREK-1 membrane targeting in the heart. Cardiovascular research 42 24445605
2011 The stretch-dependent potassium channel TREK-1 and its function in murine myometrium. The Journal of physiology 41 21224218
2016 pH-sensitive K(+) channel TREK-1 is a novel target in pancreatic cancer. Biochimica et biophysica acta 40 27443495
2016 TREK-1 (K2P2.1) K+ channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control. Basic research in cardiology 40 28005193
2015 Differential sensitivity of TREK-1, TREK-2 and TRAAK background potassium channels to the polycationic dye ruthenium red. British journal of pharmacology 39 25409575
2010 TREK-1 K(+) channels in the cardiovascular system: their significance and potential as a therapeutic target. Cardiovascular therapeutics 39 20946320
2016 Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits. The Journal of biological chemistry 38 27129242
2009 Support for the involvement of the KCNK2 gene in major depressive disorder and response to antidepressant treatment. Pharmacogenetics and genomics 38 19741570
2003 Modulation of native TREK-1 and Kv1.4 K+ channels by polyunsaturated fatty acids and lysophospholipids. The Journal of membrane biology 38 14724761
2018 Characterization of temperature-sensitive leak K+ currents and expression of TRAAK, TREK-1, and TREK2 channels in dorsal root ganglion neurons of rats. Molecular brain 37 29980241
2016 Genetic Deletion of TREK-1 or TWIK-1/TREK-1 Potassium Channels does not Alter the Basic Electrophysiological Properties of Mature Hippocampal Astrocytes In Situ. Frontiers in cellular neuroscience 37 26869883
2013 Cardiac expression and atrial fibrillation-associated remodeling of K₂p2.1 (TREK-1) K⁺ channels in a porcine model. Life sciences 37 24345461
2011 A human TREK-1/HEK cell line: a highly efficient screening tool for drug development in neurological diseases. PloS one 36 22022421
2012 Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells. American journal of physiology. Lung cellular and molecular physiology 35 23275623
2006 Expression of the mechanosensitive 2PK+ channel TREK-1 in human osteoblasts. Journal of cellular physiology 35 16250016
2011 Changes in lipid-sensitive two-pore domain potassium channel TREK-1 expression and its involvement in astrogliosis following cerebral ischemia in rats. Journal of molecular neuroscience : MN 34 21789545
2010 Role of TREK-1 potassium channel in bladder overactivity after partial bladder outlet obstruction in mouse. The Journal of urology 34 20022044
2007 Potent inhibition of native TREK-1 K+ channels by selected dihydropyridine Ca2+ channel antagonists. The Journal of pharmacology and experimental therapeutics 34 17622574
2011 Regulation and function of the two-pore-domain (K2P) potassium channel Trek-1 in alveolar epithelial cells. American journal of physiology. Lung cellular and molecular physiology 33 21949155
2017 Hyperoxia treatment of TREK-1/TREK-2/TRAAK-deficient mice is associated with a reduction in surfactant proteins. American journal of physiology. Lung cellular and molecular physiology 32 28839101
2018 MiR-183-5p Alleviates Chronic Constriction Injury-Induced Neuropathic Pain Through Inhibition of TREK-1. Neurochemical research 31 29736614
2003 Inhibition of human TREK-1 channels by bupivacaine. Anesthesia and analgesia 31 12760993
2011 Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1. Acta pharmacologica Sinica 30 21293470
2011 Cochlin induced TREK-1 co-expression and annexin A2 secretion: role in trabecular meshwork cell elongation and motility. PloS one 30 21886777
2020 Mechanosensitive TREK-1 two-pore-domain potassium (K2P) channels in the cardiovascular system. Progress in biophysics and molecular biology 29 32553901
2017 Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Frontiers in pharmacology 28 28955242
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
2004 Caffeic acid esters activate TREK-1 potassium channels and inhibit depolarization-dependent secretion. Molecular pharmacology 28 14978238
2019 Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels. Biochimica et biophysica acta. Biomembranes 27 31672538
2013 An increased TREK-1-like potassium current in ventricular myocytes during rat cardiac hypertrophy. Journal of cardiovascular pharmacology 27 23232841
2014 The 2-pore domain potassium channel TREK-1 regulates stretch-induced detachment of alveolar epithelial cells. PloS one 26 24586773
2010 Cerebrovascular responses in mice deficient in the potassium channel, TREK-1. American journal of physiology. Regulatory, integrative and comparative physiology 26 20357027
2014 Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. Critical care medicine 25 25126877
2013 2-Aminoethoxydiphenyl borate activates the mechanically gated human KCNK channels KCNK 2 (TREK-1), KCNK 4 (TRAAK), and KCNK 10 (TREK-2). Frontiers in pharmacology 25 23720627
2020 K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury. Scientific reports 24 33319831
2019 TREK-1 Null Impairs Neuronal Excitability, Synaptic Plasticity, and Cognitive Function. Molecular neurobiology 24 31728930
2017 Deficiency of TREK-1 potassium channel exacerbates secondary injury following spinal cord injury in mice. Journal of neurochemistry 24 28192611
2017 Interaction of cochlin and mechanosensitive channel TREK-1 in trabecular meshwork cells influences the regulation of intraocular pressure. Scientific reports 24 28352076
2004 Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels. Neuropharmacology 24 14996553
2004 Developmental expression of two-pore domain K+ channels, TASK-1 and TREK-1, in the rat cochlea. Neuroreport 24 15094499
2013 Regulation of Monocyte Chemotactic Protein-1 secretion by the Two-Pore-Domain Potassium (K2P) channel TREK-1 in human alveolar epithelial cells. American journal of translational research 23 23977412
2003 Corticotropin induces the expression of TREK-1 mRNA and K+ current in adrenocortical cells. Molecular pharmacology 23 12815169
2020 The correlation and role analysis of KCNK2/4/5/15 in Human Papillary Thyroid Carcinoma microenvironment. Journal of Cancer 22 32742463
2018 eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data. Brain structure & function 22 30519892
2011 TREK-1 isoforms generated by alternative translation initiation display different susceptibility to the antidepressant fluoxetine. Neuropharmacology 22 21740918
2009 cAMP analogs and their metabolites enhance TREK-1 mRNA and K+ current expression in adrenocortical cells. Molecular pharmacology 22 20028740
2018 Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator. PloS one 21 30110354
2015 Arginine Vasopressin Potentiates the Stimulatory Action of CRH on Pituitary Corticotropes via a Protein Kinase C-Dependent Reduction of the Background TREK-1 Current. Endocrinology 21 26248219
2013 TREK-1 currents in smooth muscle cells from pregnant human myometrium. American journal of physiology. Cell physiology 21 23804201
2013 The thermosensitive potassium channel TREK-1 contributes to coolness-evoked responses of Grueneberg ganglion neurons. Cellular and molecular neurobiology 21 24101433
2013 A splice variant of the two-pore domain potassium channel TREK-1 with only one pore domain reduces the surface expression of full-length TREK-1 channels. Pflugers Archiv : European journal of physiology 21 24196565
2012 Expression of the two pore domain potassium channel TREK-1 in human intervertebral disc cells. Current stem cell research & therapy 21 22563662
2012 Variants of stretch-activated two-pore potassium channel TREK-1 associated with preterm labor in humans. Biology of reproduction 21 22811574
2007 Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1. Medical hypotheses 20 17703894
2006 VOCCs and TREK-1 ion channel expression in human tenocytes. American journal of physiology. Cell physiology 20 17035301
2004 Postnatal changes in TASK-1 and TREK-1 expression in rat brain stem and cerebellum. Neuroreport 20 15167558
2017 Activation of TREK-1, but Not TREK-2, Channel by Mood Stabilizers. International journal of molecular sciences 19 29156592

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