Affinage

KCNK18

Potassium channel subfamily K member 18 · UniProt Q7Z418

Length
384 aa
Mass
43.7 kDa
Annotated
2026-06-10
74 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNK18 encodes TRESK (K2P18.1), a two-pore-domain background K+ channel that produces an outwardly-rectifying, time-independent, non-inactivating K+-selective current and serves as a dominant background K+ conductance in dorsal root and trigeminal ganglion sensory neurons, where it sets excitability and suppresses nociceptor firing (PMID:12754259, PMID:16495368, PMID:24466320). The channel's defining regulatory feature is reversible phosphorylation of its large intracellular loop: it is held inhibited in the resting state by phosphorylation of Ser-264 (a PKA site and 14-3-3 binding site) and of a Ser-274/276/279 cluster targeted by MARK1/2/3 kinases, and is activated several-fold when cytoplasmic calcium rises and the phosphatase calcineurin docks to non-catalytic PQIVID/PQIIIS and LQLP motifs in the loop to dephosphorylate these serines (PMID:14981085, PMID:16569637, PMID:18397886, PMID:20215114, PMID:22145024, PMID:25202008). Calcineurin-independent activation also occurs through novel-type PKC isoforms (η, ε) that drive indirect Ser-264 dephosphorylation (PMID:30992311). TRESK activity is further tuned by N-linked glycosylation required for surface expression, membrane stretch, anionic phospholipids acting at a human-specific cytoplasmic site, the intracellular C-terminal region as a gating determinant, and NDFIP1–Nedd4-mediated ubiquitination that suppresses current (PMID:20006580, PMID:23691227, PMID:30039335, PMID:37084812, PMID:39201565). TRESK assembles as homodimers and as functional heterodimers with TREK-2 in somatosensory neurons, and its loss enhances mechanical, cold, and itch sensitivity and potentiates TRPV1/CGRP signaling (PMID:31919847, PMID:32641496, PMID:33525904, PMID:40062712). A dominant-negative frameshift mutation (F139WfsX24) that abolishes TRESK function and, via alternative translation initiation, generates a TRESK-MT2 fragment that additionally inhibits TREK1/TREK2 is causally linked to familial migraine with aura, with CRISPR correction in patient iPSC nociceptors reversing the associated hyperexcitability (PMID:20871611, PMID:30573346, PMID:31742594).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 2003 High

    Established the molecular and biophysical identity of TRESK, defining it as a background K+ channel and resolving what kind of conductance KCNK18 produces.

    Evidence Whole-cell and patch-clamp electrophysiology with pharmacology in heterologous systems

    PMID:12754259

    Open questions at the time
    • No physiological regulator or native cellular role identified
    • Pharmacology limited to blockers without endogenous modulators
  2. 2004 High

    Showed that calcium activates TRESK indirectly through calcineurin acting on intracellular serines, answering how a background channel is dynamically regulated by signaling.

    Evidence Voltage clamp in Xenopus oocytes, microinjection, calcineurin pharmacology, and alanine-scanning mutagenesis (Ser-276); parallel cloning of the mouse ortholog confirmed conserved biophysics

    PMID:14981085 PMID:15123670

    Open questions at the time
    • Mechanism of calcineurin recruitment to the channel not yet defined
    • Kinases that re-phosphorylate the sites unknown
  3. 2004 High

    Identified TRESK as a target of clinical anesthetics, linking the channel to drug-modifiable excitability.

    Evidence Voltage-clamp in oocytes and COS-7 cells with systematic anesthetic and local-anesthetic panels

    PMID:15562060

    Open questions at the time
    • Binding site for volatile anesthetics not mapped
    • In vivo relevance not established
  4. 2005 High

    Defined metal-ion pharmacology and a molecular determinant (His132) of species-specific zinc sensitivity, providing tools to distinguish TRESK from other K2P channels.

    Evidence Voltage clamp, outside-out single-channel recordings, and H132 mutagenesis with cross-species comparison

    PMID:16354767

    Open questions at the time
    • Physiological role of zinc/mercury modulation unknown
  5. 2006 High

    Resolved the molecular basis of calcineurin docking, demonstrating that an NFAT-like PQIVID motif recruits the phosphatase, explaining how a non-substrate-like channel is targeted by calcineurin.

    Evidence GST pulldown with purified proteins, VIVIT peptide microinjection, mutagenesis, and voltage clamp

    PMID:16569637

    Open questions at the time
    • A second docking determinant not yet recognized
    • Re-phosphorylating kinases still unidentified
  6. 2006 High

    Demonstrated that native TRESK-like channels carry a substantial fraction of background K+ conductance in DRG neurons, anchoring the channel's physiological role in sensory neurons.

    Evidence Single-channel patch clamp in rat DRG neurons with RT-PCR and pharmacological identity matching

    PMID:16495368

    Open questions at the time
    • Channel identity inferred from biophysics/pharmacology, not genetic ablation
    • Contribution to behavior untested
  7. 2007 High

    Genetic loss-of-function established TRESK's contribution to DRG action-potential properties and excitability, and mapped a pH-sensitivity residue near the selectivity filter.

    Evidence Patch/current clamp in TRESK[G339R] knockout DRG neurons plus mutagenesis and in situ hybridization

    PMID:17962323

    Open questions at the time
    • Resting membrane potential unchanged, implying redundancy
    • Behavioral consequences not assessed
  8. 2008 High

    Identified 14-3-3γ/η as phospho-Ser-264-dependent loop partners controlling the kinetics of calcineurin regulation, adding a layer of temporal control to channel gating.

    Evidence Voltage clamp with 14-3-3 coexpression, tethered constructs, competing phosphopeptide, and S264 mutagenesis

    PMID:18397886

    Open questions at the time
    • Kinase generating phospho-Ser-264 not yet defined
    • Isoform selectivity in native neurons untested
  9. 2010 High

    Dissected two distinct inhibitory phosphorylation pathways (PKA at Ser-264 and a separate kinase at the Ser-274/276/279 cluster) and showed cross-talk via 14-3-3, building the integrated phospho-regulatory model.

    Evidence Voltage clamp in oocytes with phosphomimetic and cluster mutagenesis and coexpression; pharmacological GPCR activation in DRG identified upstream agonists

    PMID:18190784 PMID:20215114

    Open questions at the time
    • Identity of the Ser-274/276/279 kinase still unknown at this stage
    • PKA recruitment mechanism unclear
  10. 2009 High

    Established N-linked glycosylation as a requirement for TRESK surface expression, defining a post-translational checkpoint for channel availability.

    Evidence Mutagenesis with Western blot, voltage clamp, and confocal imaging of GFP-tagged channel

    PMID:20006580

    Open questions at the time
    • Trafficking machinery downstream of glycosylation not identified
  11. 2010 High

    Linked a dominant-negative TRESK frameshift mutation to familial migraine with aura, providing the first human disease connection and a mechanism (suppression of wild-type subunits).

    Evidence Voltage clamp with wild-type/mutant co-expression and genetic linkage in a large pedigree

    PMID:20871611

    Open questions at the time
    • How loss of a DRG/TG channel produces aura not explained
    • Penetrance and modifiers unknown
  12. 2010 Medium

    In vivo knockout linked TRESK quantitatively to volatile anesthetic sensitivity while showing it is dispensable for baseline CNS function.

    Evidence Homologous-recombination knockout mice with minimum alveolar concentration measurement

    PMID:21042202

    Open questions at the time
    • Small effect size implies redundancy with other K2P channels
    • Single-lab in vivo result
  13. 2011 High

    Identified MARK1/2/3 as the kinases phosphorylating the Ser-274/276/279 cluster, completing the assignment of the two inhibitory phosphorylation pathways.

    Evidence Voltage clamp with MARK isoform coexpression and cluster mutagenesis, with selectivity testing of multiple kinases

    PMID:22145024

    Open questions at the time
    • Physiological signals that engage MARK kinases on TRESK unknown
    • Direct phosphorylation not confirmed biochemically in this assay
  14. 2012 High

    Distinguished a migraine-causing frameshift mutant from a functionally null but non-migraine C110R variant, showing that loss of TRESK current alone is insufficient for disease and demanding a further mechanism.

    Evidence Voltage clamp characterization of missense and frameshift variants in oocytes with epidemiological context

    PMID:22355750 PMID:23904616

    Open questions at the time
    • What distinguishes the frameshift from C110R molecularly unresolved at this point
    • Native neuronal consequences then incompletely tested
  15. 2014 High

    Resolved a second calcineurin docking site (LQLP) acting as a calcium-sensitivity determinant distinct from the affinity-setting PQIIIS, refining the bipartite recruitment model.

    Evidence Voltage clamp with LQLP/PQIIIS mutagenesis and calcium calibration in oocytes

    PMID:25202008

    Open questions at the time
    • Structural basis of dual docking not determined
  16. 2014 Medium

    Demonstrated tubulin binding to the TRESK loop overlapping the 14-3-3 site, suggesting cytoskeletal cross-regulation of the channel.

    Evidence Affinity chromatography, brain-cytosol pulldown, truncation, and competitive binding in vitro

    PMID:24830385

    Open questions at the time
    • Interaction in living cells not established
    • Functional consequence on current not shown
  17. 2014 High

    Gain-of-function in native TG neurons confirmed TRESK as a brake on nociceptor firing, including capsaicin-evoked spiking, and comparative variant work tied excitability changes to the migraine mutant.

    Evidence TRESK overexpression with patch/current clamp and Western blot in TG neurons; parallel C110R vs frameshift comparison in TG neurons

    PMID:24466320 PMID:24805079

    Open questions at the time
    • Endogenous stimuli driving these changes in vivo not defined
  18. 2013 Medium

    Showed TRESK is mechanosensitive, responding to stretch and osmotic changes, broadening its role as an integrator of physical and chemical stimuli.

    Evidence Whole-cell and single-channel recordings in F-11 cells and trigeminal neurons under shear, swelling, and shrinkage

    PMID:23691227

    Open questions at the time
    • Molecular mechanism of mechanotransduction unmapped
    • Physiological role of stretch sensitivity untested in vivo
  19. 2015 High

    Identified LPA-receptor signaling as a physiological GPCR input that activates TRESK to attenuate nociceptor excitability, with knockout confirming specificity.

    Evidence Co-expression voltage clamp plus patch/current clamp in TRESK-wt and -ko DRG neurons

    PMID:26224542

    Open questions at the time
    • Signaling steps from LPA receptor to channel dephosphorylation not fully mapped
  20. 2018 High

    Resolved why only the frameshift mutation causes migraine: alternative translation initiation produces TRESK-MT2, which co-assembles with and inhibits TREK1/TREK2, providing a gain-of-pathology mechanism beyond simple TRESK loss.

    Evidence In vitro translation, co-IP, patch clamp in heterologous and primary neurons, and in vivo rodent behavior

    PMID:30573346

    Open questions at the time
    • Structural basis of TRESK-MT2/TREK heterodimer inhibition not determined
    • Human in vivo validation pending
  21. 2018 High

    Defined anionic phospholipids as a human-specific activating input acting at a cytoplasmic loop site, and novel-type PKC as a calcineurin-independent activator, expanding the regulatory repertoire.

    Evidence MLV binding, mutagenesis, chimeras and GPCR experiments for phospholipids; PKC coexpression, mutagenesis, and Phos-tag SDS-PAGE for PKC pathway

    PMID:30039335 PMID:30992311

    Open questions at the time
    • Why phospholipid sensitivity is species-restricted not explained
    • Identity of the PKC-inhibited Ser-264 kinase unknown
  22. 2018 Medium

    Connected TRESK transcriptional downregulation to a tumor VEGF–DSCR1–calcineurin–NFAT axis as a driver of cancer pain, extending TRESK regulation to gene-expression control.

    Evidence In vivo bone metastasis model with DRG overexpression/knockdown, patch clamp, IHC, and pathway manipulation

    PMID:30327410

    Open questions at the time
    • Multi-step pathway from single lab
    • Direct NFAT regulation of the KCNK18 promoter not shown
  23. 2019 High

    Knockout phenotyping defined modality-specific sensory roles, showing TRESK constrains mechanical and cold (but not heat) sensitivity and nociceptor excitability.

    Evidence Behavioral testing, skin-nerve C-fiber recordings, and patch clamp of isolated nociceptors in knockout mice

    PMID:31919847

    Open questions at the time
    • Cellular basis of modality specificity unresolved
  24. 2019 High

    Provided causal human evidence that the migraine frameshift mutation drives nociceptor hyperexcitability, since CRISPR correction reversed it, and validated cloxyquin as a corrective activator.

    Evidence iPSC-derived nociceptors with CRISPR-Cas9 correction, patch clamp, and an in vitro human pain model

    PMID:31742594

    Open questions at the time
    • Link from nociceptor hyperexcitability to migraine aura still indirect
  25. 2020 High

    Demonstrated functional TRESK/TREK-2 heterodimers in somatosensory neurons, revealing that native background conductance is a composite channel with mixed regulatory and pharmacological properties.

    Evidence Covalently linked tandem constructs, voltage clamp, and native single-channel recordings with TREK-2-selective T2A3

    PMID:32641496

    Open questions at the time
    • Stoichiometry and relative abundance of heterodimers in vivo not quantified
  26. 2021 High

    Showed TRESK gates TRPV1-mediated calcium signaling and CGRP release, mechanistically linking the channel to peripheral nociceptive and migraine-relevant signaling.

    Evidence Calcium imaging, CGRP release and meningeal blood-flow assays with pharmacology confirmed in knockout mice

    PMID:33525904

    Open questions at the time
    • Whether TRESK and TRPV1 physically interact not addressed
  27. 2023 High

    Identified the intracellular C-terminal region as a major gating determinant whose membrane interaction sets channel activity, deepening the structural understanding of TRESK regulation.

    Evidence Voltage clamp with the ENaR normalization method, single-channel recordings, and iCtr mutagenesis in oocytes

    PMID:37084812

    Open questions at the time
    • High-resolution structure of the iCtr–membrane interface lacking
  28. 2024 High

    Established NDFIP1–Nedd4-mediated ubiquitination as a degradative/regulatory pathway suppressing TRESK current, adding protein turnover to the regulatory model.

    Evidence Co-IP, ubiquitination assay, PPxY-motif mutagenesis, dominant-negative Nedd4, and voltage clamp in oocytes

    PMID:39201565

    Open questions at the time
    • Physiological/disease contexts engaging NDFIP1-Nedd4 on TRESK unknown
    • Confirmation in native neurons pending
  29. 2025 High

    Extended TRESK's role to itch, showing it constrains MrgprA3+ pruriceptor excitability and chronic itch, broadening its sensory remit beyond pain.

    Evidence Knockout mice with itch behavior, MrgprA3+ neuron recordings, pharmacological activation, and chronic itch models

    PMID:40062712

    Open questions at the time
    • Stimulus specificity (chloroquine but not histamine) mechanistically unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRESK's diverse regulatory inputs are integrated at the structural level and how loss of a peripheral sensory K+ channel produces centrally-perceived migraine aura remain unresolved.
  • No high-resolution structure of the regulated intracellular loop/iCtr
  • Mechanistic link from nociceptor hyperexcitability to migraine aura unestablished
  • Re-phosphorylating kinase for Ser-264 not definitively identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3
Partners
MARK2NDFIP1NEDD4PPP3CATREK-2TREK1YWHAGYWHAH
Complex memberships
TRESK homodimerTRESK/TREK-2 heterodimer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TRESK (KCNK18) is a novel two-pore domain K+ channel with two pore-forming domains and four transmembrane domains that functions as a background K+ channel producing outward-rectifying, time-independent, non-inactivating K+-selective current; it is inhibited by Ba2+, propafenone, glyburide, lidocaine, quinine, quinidine, triethanolamine, unsaturated free fatty acids (arachidonic acid, DHA), and extreme pH changes. Electrophysiology (whole-cell and patch clamp) in heterologous expression systems; pharmacological analysis The Journal of biological chemistry High 12754259
2004 TRESK is activated 5–15-fold by cytoplasmic calcium elevation (via Ca2+-mobilizing receptors, ionomycin, IP3 microinjection, or direct Ca2+ microinjection). Activation requires cytoplasmic factors (direct Ca2+ application to inside-out patches had no effect) and is mediated by the calcium/calmodulin-dependent phosphatase calcineurin; cyclosporin A and FK506 completely blocked TRESK activation. Coexpression of constitutively active calcineurin increased basal TRESK current. Alanine-scanning mutagenesis identified serine 276 as the major functional target of calcineurin in TRESK. Two-electrode voltage clamp in Xenopus oocytes; inside-out patch clamp; microinjection of IP3, Ca2+, EGTA; pharmacology (cyclosporin A, FK506); alanine-scanning mutagenesis The Journal of biological chemistry High 14981085
2004 TRESK-2 (KCNK18 mouse ortholog) is a functional K2P channel producing time-independent, non-inactivating, K+-selective background current with single-channel conductance of ~13–16 pS; it is inhibited by quinidine, arachidonate, and acid, but not by TEA, apamin, 4-AP, or glybenclamide, and is unaffected by intracellular GTPγS. Whole-cell patch clamp and single-channel recordings in COS-7 cells; inside-out patches; Northern blot The Journal of biological chemistry High 15123670
2004 Human TRESK currents are potently activated (up to 3-fold) by clinical concentrations of volatile anesthetics (isoflurane, halothane, sevoflurane, desflurane) but not by nonanesthetic compounds (nonimmobilizers) or most IV anesthetics (etomidate, thiopental, propofol). Local anesthetics inhibit TRESK in a concentration-dependent manner. Whole-cell voltage-clamp and patch-clamp in Xenopus oocytes and COS-7 cells Anesthesia and analgesia High 15562060
2005 Zinc (Zn2+) and mercuric ions (Hg2+) are selective inhibitors of mouse TRESK among K2P channels (IC50 <10 µM), acting in a membrane-delimited manner on the channel itself (confirmed by outside-out single-channel recordings). Human TRESK is resistant to Zn2+ but blocked by Hg2+; His132 of mouse TRESK is partly responsible for the species difference in zinc sensitivity. Mibefradil also inhibited TRESK but with less selectivity. Two-electrode voltage clamp in Xenopus oocytes; outside-out patch clamp in COS-7 cells; site-directed mutagenesis (H132 substitution) Molecular pharmacology High 16354767
2006 Calcineurin activates TRESK through both its catalytic (phosphatase) activity and a non-catalytic docking interaction. TRESK's intracellular loop contains a PQIVID sequence homologous to the NFAT calcineurin-binding consensus (PXIXIT). Mutations of PQIVID to PQIVIA, PQIVAD, or PQAVAD progressively reduced calcium-dependent activation. VIVIT peptide microinjection eliminated TRESK activation. GST-TRESK intracellular loop pulled down constitutively active calcineurin in vitro; wild-type calcineurin was recruited in the presence of Ca2+/calmodulin; PQAVAD mutation and VIVIT peptide abrogated this binding. Two-electrode voltage clamp in Xenopus oocytes; site-directed mutagenesis; VIVIT peptide microinjection; GST pulldown assay with purified proteins The Journal of biological chemistry High 16569637
2006 TRESK-like (14 pS) channels and TREK-2-like (50 pS) channels together account for >95% of background K+ conductance in DRG neurons at 37°C; the TRESK-like channel contributes ~16% of resting K+ current. Native TRESK channels in DRG neurons share biophysical and pharmacological properties (inhibition by acid, arachidonic acid) with cloned TRESK. Single-channel patch clamp (cell-attached and inside-out) in rat DRG neurons; RT-PCR American journal of physiology. Cell physiology High 16495368
2007 Mouse TRESK channels contribute approximately 20% of the standing outward current (IKso) in DRG neurons. TRESK functional knockout mice (TRESK[G339R]) show no change in resting membrane potential but display significantly altered action potential duration, amplitude of after-hyperpolarization, and increased excitability (reduced rheobase). A single histidine residue adjacent to the GYG selectivity filter confers pH sensitivity to mouse (but not human) TRESK. Whole-cell patch clamp and current-clamp in DRG neurons from TRESK functional knockout mice vs. wild-type; site-directed mutagenesis; in situ hybridization The Journal of physiology High 17962323
2008 14-3-3 proteins (γ and η isoforms) directly bind to the intracellular loop of TRESK and control the kinetics of calcineurin-dependent regulation by slowing the return of K+ current to resting state after activation. Phosphorylation of serine 264 in mouse TRESK is required for 14-3-3η binding. A tethered 14-3-3η construct retained the same regulatory effect, demonstrating direct action on TRESK. Competing phosphopeptide (Ser(P)-Raf259) abolished the 14-3-3 effect. β, ζ, ε, σ, and τ isoforms of 14-3-3 did not significantly influence TRESK regulation. Two-electrode voltage clamp in Xenopus oocytes; coexpression of 14-3-3 isoforms and dominant-negative constructs; phosphopeptide microinjection; site-directed mutagenesis (S264) The Journal of biological chemistry High 18397886
2008 TRESK in DRG neurons is activated by GPCR agonists (acetylcholine, glutamate, histamine) and inhibited by lamotrigine (~50% inhibition at 30 µM in COS-7 cells). Native TRESK in DRG shares pharmacological properties (inhibited by acid, arachidonic acid; not by zinc) with cloned TRESK. Whole-cell patch clamp in DRG neurons and COS-7 cells transfected with mouse TRESK; pharmacological analysis Biochemical and biophysical research communications Medium 18190784
2009 N-linked glycosylation at a single residue in the first external loop is required for proper cell surface expression of TRESK. Glycosylation-deficient mutants show >80% reduction in current amplitude and >50% reduction in cell surface fluorescence in confocal microscopy of GFP-tagged TRESK. Site-directed mutagenesis; Western immunoblotting; two-electrode voltage clamp in Xenopus oocytes; confocal microscopy of GFP-tagged constructs Biochemical and biophysical research communications High 20006580
2010 TRESK is inhibited by phosphorylation via two distinct pathways converging on the intracellular loop: (1) PKA phosphorylates Ser-264 (the 14-3-3 binding site), accelerating current return to resting state; (2) a separate kinase phosphorylates the cluster of Ser-274, Ser-276, and Ser-279. 14-3-3 binding to Ser-264 additionally inhibits the kinase targeting the Ser-274/276/279 cluster, independently of direct TRESK–14-3-3 interaction. Two-electrode voltage clamp in Xenopus oocytes; site-directed mutagenesis (S264E, S276E, S274/276/279 cluster); coexpression experiments The Journal of biological chemistry High 20215114
2010 The TRESK frameshift mutation F139WfsX24 causes complete loss of TRESK channel function, and the mutant subunit suppresses wild-type TRESK channel function through a dominant-negative mechanism (demonstrated in Xenopus oocytes). The mutation segregates perfectly with typical migraine with aura in a large pedigree. Two-electrode voltage clamp in Xenopus oocytes; co-expression of wild-type and mutant subunits; genetic linkage analysis Nature medicine High 20871611
2010 TRESK knockout mice show a discrete 8% increase in isoflurane minimum alveolar concentration compared to wild-type, supporting a contribution of TRESK to volatile anesthetic sensitivity, though TRESK alone is not critical for baseline CNS function. Homologous recombination knockout mice; minimum alveolar concentration determination for volatile anesthetics Anesthesiology Medium 21042202
2011 MARK1, MARK2, and MARK3 (microtubule affinity-regulating kinases; PAR-1/MARK family) inhibit TRESK by phosphorylating the cluster of Ser-274, Ser-276, and Ser-279 in the intracellular loop, accelerating return of TRESK current to resting state after calcineurin-dependent activation. MARK2 does not phosphorylate Ser-264 (the 14-3-3 binding site). Several other serine-threonine kinases tested had no effect. Two-electrode voltage clamp in Xenopus oocytes; coexpression of MARK isoforms; site-directed mutagenesis of the S274/276/279 cluster PloS one High 22145024
2012 The mutant TRESK F139WfsX24 subunit exerts dominant-negative effects on whole-cell TRESK current AND on the level of TRESK channels at the plasma membrane through heterodimerization with wild-type subunits in HEK293T cells. Expression of mutant TRESK in mouse trigeminal ganglion neurons decreases lamotrigine-sensitive K+ current and causes hyperexcitability (higher input resistance, lower current threshold for action potentials, higher spike frequency). Whole-cell patch clamp in HEK293T cells and cultured trigeminal ganglion neurons; surface biotinylation assay; current-clamp recordings The Journal of neuroscience High 23904616
2012 The TRESK C110R variant causes complete loss of function and dominant-negative suppression of wild-type TRESK current in Xenopus oocytes, similar to the migraine-associated frameshift mutant, yet C110R is present in both migraine and control cohorts, indicating that loss of TRESK function alone is not sufficient to cause migraine. Two-electrode voltage clamp in Xenopus oocytes; functional characterization of missense variants Scientific reports High 22355750
2013 Membrane stretch (laminar shear stress, hypotonic cell swelling) increases TRESK currents by 22–40%, while cell shrinkage (hypertonic solution) decreases them. Negative pressure applied to trigeminal neurons increases TRESK channel open probability 1.51-fold. TRESK currents are additively inhibited by arachidonic acid, acidic pH, and hypertonic stimulation. Whole-cell patch clamp and single-channel recordings in heterologous systems (F-11 cells) and trigeminal neurons; osmotic swelling/shrinkage; shear stress application PloS one Medium 23691227
2013 Cloxyquin (5-chloroquinolin-8-ol) activates TRESK with an EC50 of 3.8 µM (thallium flux assay) and approximately 2-fold increase in outward current (patch clamp), with good selectivity against other potassium channels tested. Thallium flux assay; whole-cell patch clamp electrophysiology in U2OS cells Biochemical and biophysical research communications Medium 24383077
2014 Human TRESK contains a second calcineurin docking site, LQLP, in its intracellular loop in addition to PQIIIS. The LQLP→AQAP mutation alone did not change the amplitude of TRESK activation at high calcium but slowed the response and prevented activation by modest calcium elevation. Combined mutations of both PQIIIS and LQLP were required to eliminate calcium-dependent regulation. LQLP acts as a distinct determinant of calcium sensitivity, separate from the affinity-determining role of PQIIIS. Two-electrode voltage clamp in Xenopus oocytes; site-directed mutagenesis of LQLP and PQIIIS motifs; calcium calibration experiments The Journal of biological chemistry High 25202008
2014 Overexpression of TRESK in mouse trigeminal ganglion neurons (via lipofectamine transfection) produces a 2-fold increase in lamotrigine-sensitive persistent K+ current and total background K+ current, with decreased input resistance and 2-fold higher current threshold for action potential initiation in both IB4+ and IB4- neurons. TRESK overexpression also inhibits capsaicin-evoked action potentials. Whole-cell patch clamp and current-clamp in cultured mouse TG neurons overexpressing TRESK; Western blot for TRESK protein levels PloS one High 24466320
2014 The non-migraine-associated C110R variant reduces endogenous TRESK currents in trigeminal ganglion neurons, but to a significantly smaller degree than the migraine-associated frameshift mutant, and only the frameshift mutant (not C110R) produces significant hyperexcitability of TG neurons. Whole-cell patch clamp in HEK293T cells and cultured mouse TG neurons expressing C110R or mutant TRESK; current-clamp recordings Journal of neurophysiology High 24805079
2014 Tubulin binds specifically to the intracellular loop of TRESK in vitro at a 16 amino acid sequence (LVLGRLSYSIISNLDE). The tubulin-binding site overlaps with the PKA-dependent 14-3-3 docking region, and 14-3-3 competes with tubulin for binding to the TRESK cytoplasmic loop. Affinity chromatography with GST-TRESK loop as bait; pulldown from mouse brain cytosol; successive truncation experiments; competitive binding assay PloS one Medium 24830385
2015 Lysophosphatidic acid (LPA) activates TRESK through LPA receptors in DRG neurons, increasing background K+ current (IKso) and attenuating nociceptor excitability. In TRESK knockout DRG neurons, LPA does not increase IKso, confirming TRESK mediates this effect. LPA simultaneously activates both TRPV1 (depolarizing) and TRESK (hyperpolarizing) in co-expression experiments. Two-electrode voltage clamp in Xenopus oocytes co-expressing TRESK and LPA receptors; whole-cell patch clamp in DRG neurons from TRESK-wt and TRESK-ko mice; current-clamp recordings Scientific reports High 26224542
2017 Cloxyquin selectively activates mouse and human TRESK (~4-fold) in a state-dependent manner: it potently activates TRESK in the resting (phosphorylated) state but does not further activate TRESK after calcineurin-dependent activation or in constitutively active mutants (S276A, F156A, F364A). Cloxyquin activates TRESK via a Ca2+/calcineurin-independent mechanism and is selective for TRESK within the K2P family. It also activates background K+ current in a subpopulation of DRG neurons. Two-electrode voltage clamp in Xenopus oocytes; whole-cell patch clamp in mouse DRG neurons; site-directed mutagenesis; pharmacological selectivity screen of K2P channels British journal of pharmacology High 28419410
2018 The TRESK frameshift mutation F139WfsX24 (TRESK-MT) generates via alternative translation initiation (fsATI) a second protein fragment, TRESK-MT2, from the same mRNA. TRESK-MT2 co-assembles with TREK1 and TREK2 and inhibits their activity, increasing trigeminal sensory neuron excitability and producing a migraine-like phenotype in rodents. The non-migraine-associated C110R mutant does not produce fsATI or TRESK-MT2, explaining the differential migraine association of the two mutations. In vitro translation assays; co-immunoprecipitation; patch clamp electrophysiology in heterologous cells and primary neurons; in vivo rodent behavioral assays Neuron High 30573346
2018 Anionic phospholipids (PIP2 analog, Folch fraction MLVs) activate human TRESK but not rat TRESK through electrostatic binding to a 14 amino acid sequence in the large cytoplasmic loop at the membrane-cytosol interface. Disruption of this sequence inhibits hTRESK. Replacing the equivalent rat sequence with the human anionic phospholipid-binding site confers PIP2 sensitivity to rat TRESK. Gq/11-linked GPCR stimulation (with calcineurin inhibition) reduces hTRESK current, consistent with PIP2 hydrolysis-dependent inhibition. Binding assay with multilamellar vesicles; whole-cell patch clamp; site-directed mutagenesis; chimeric channel constructs; GPCR stimulation experiments Molecular neurobiology High 30039335
2018 Tumor-produced VEGF activates VEGFR2 on DRG neurons, increasing DSCR1 (calcineurin inhibitor) abundance, which reduces calcineurin-mediated NFAT activation and thereby decreases TRESK transcription, resulting in sensory neuron hyperexcitability and pain. Intrathecal calcineurin restored TRESK expression and abolished DRG hyperexcitability and pain in tumor-bearing rats. In vivo bone metastasis model; TRESK overexpression/knockdown in DRG; patch clamp; immunohistochemistry; VEGF pathway manipulation Science signaling Medium 30327410
2019 Novel-type PKC isoforms η and ε activate human TRESK by indirect dephosphorylation of Ser-264 via inhibition of the kinase that rephosphorylates this site, not via calcineurin. S264A and S264E mutations abolished PMA-induced TRESK activation. Mutations of calcineurin-binding sites did not prevent PKC-dependent activation. PKC-dependent dephosphorylation of TRESK was confirmed by Phos-tag SDS-PAGE. Two-electrode voltage clamp in Xenopus oocytes; coexpression of PKC isoforms; site-directed mutagenesis (S264A/E, calcineurin-binding site mutations); Phos-tag SDS-PAGE Molecular pharmacology High 30992311
2019 TRESK knockout mice show enhanced mechanical and cold sensitivity in behavioral tests and in skin nerve C-fiber recordings, without altered heat sensitivity. TRESK deletion also enhances excitability of isolated nociceptors and exacerbates cold allodynia (but not thermal hyperalgesia) in chronic pain states. TRESK knockout mice; behavioral testing (von Frey, cold plate, heat); skin-nerve fiber preparation; whole-cell patch clamp of isolated nociceptors The Journal of physiology High 31919847
2019 In iPSC-derived nociceptors from migraine patients with F139WfsX24 mutation, there is loss of functional TRESK at the membrane with significantly increased neuronal excitability. CRISPR-Cas9 correction of the F139WfsX24 mutation reverses the heightened excitability. C110R nociceptors show no change in excitability and preserved TRESK current. The TRESK activator cloxyquin reduces spontaneous firing of nociceptors in an in vitro human pain model. iPSC-derived nociceptors; CRISPR-Cas9 gene correction; patch clamp electrophysiology; in vitro human pain model with cloxyquin Brain : a journal of neurology High 31742594
2020 TRESK and TREK-2 subunits form functional heterodimers in primary somatosensory neurons. Using a covalently linked TRESK/TREK-2 tandem construct, the heterodimer shows an intermediate single-channel conductance between TRESK and TREK-2 homodimers, retains calcineurin-dependent regulation (conferred by the TRESK subunit), and acquires sensitivity to the TREK-2-selective activator T2A3 (conferred by the TREK-2 subunit). In trigeminal neurons, native channels with biophysical and pharmacological properties matching the TRESK/TREK-2 tandem were detected. Covalently linked tandem channel constructs; two-electrode voltage clamp in Xenopus oocytes; single-channel patch clamp in native trigeminal neurons; pharmacological characterization with TREK-2 selective activator T2A3 The Journal of biological chemistry High 32641496
2021 TRESK inhibition increases TRPV1-mediated calcium signals in DRG neurons and potentiates capsaicin-induced CGRP release from trigeminal afferents and meningeal blood flow. TRESK activation decreases capsaicin sensitivity of sensory neurons. These effects are absent in TRESK knockout animals, confirming that TRESK modulates TRPV1-mediated nociceptor function. Calcium imaging in DRG neurons; CGRP release assay from trigeminal afferents; meningeal blood flow measurement; pharmacological TRESK activation/inhibition; TRESK knockout mice Cephalalgia High 33525904
2023 The short intracellular C-terminal region (iCtr) following the fourth transmembrane segment of TRESK is a critical determinant of channel activity. Mutations of positive residues in proximal iCtr lock TRESK in a low-activity, calcineurin-insensitive state. Replacing distal iCtr with a sequence designed to interact with the inner plasma membrane surface increases TRESK activity to unprecedented levels. The ENaR (epithelial Na+ current ratio) method was developed to normalize K+ current to channel surface expression. Two-electrode voltage clamp in Xenopus oocytes; ENaR (epithelial sodium current ratio) method using ENaC as internal reference; single-channel recordings; site-directed mutagenesis of iCtr residues The Journal of biological chemistry High 37084812
2024 NDFIP1 (Nedd4 family-interacting protein 1) interacts with TRESK (confirmed by co-immunoprecipitation) and negatively regulates TRESK current. NDFIP1 coexpression induces ubiquitination of TRESK and abolishes TRESK current. Mutations in the three PPxY motifs of NDFIP1 (required for Nedd4 ubiquitin ligase binding) prevented TRESK current reduction. Dominant-negative Nedd4 partially reversed NDFIP1's effect on TRESK current. Two-electrode voltage clamp in Xenopus oocytes; co-immunoprecipitation; ubiquitination assay; site-directed mutagenesis of NDFIP1 PPxY motifs; dominant-negative Nedd4 coexpression International journal of molecular sciences High 39201565
2025 TRESK regulates the excitability of MrgprA3-expressing pruriceptors. TRESK knockout mice show enhanced firing of MrgprA3+ neurons and increased acute itch response to chloroquine (but not histamine, BAM8-22, or leukotriene C4). TRESK deletion exacerbates chronic itch in models of allergic contact dermatitis, dry skin, and imiquimod-induced psoriasis. Pharmacological TRESK activation reduces both acute and chronic itch in wild-type but not TRESK KO mice. TRESK knockout mice; behavioral itch assays; electrophysiological recordings from MrgprA3+ neurons; pharmacological TRESK activation; chronic itch mouse models Pain High 40062712

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nature medicine 255 20871611
2006 TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. American journal of physiology. Cell physiology 173 16495368
2003 A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. The Journal of biological chemistry 127 12754259
2004 The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. The Journal of biological chemistry 120 14981085
2007 TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. The Journal of physiology 112 17962323
2011 TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury. Molecular pain 110 21527011
2018 Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK. Neuron 96 30573346
2004 Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesthesia and analgesia 88 15562060
2006 Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK. The Journal of biological chemistry 84 16569637
2004 Functional expression of TRESK-2, a new member of the tandem-pore K+ channel family. The Journal of biological chemistry 74 15123670
2012 Functional analysis of missense variants in the TRESK (KCNK18) K channel. Scientific reports 64 22355750
2013 Functional analysis of a migraine-associated TRESK K+ channel mutation. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 23904616
2019 A causal role for TRESK loss of function in migraine mechanisms. Brain : a journal of neurology 47 31742594
2014 Over-expression of TRESK K(+) channels reduces the excitability of trigeminal ganglion nociceptors. PloS one 47 24466320
2011 Migraine: Role of the TRESK two-pore potassium channel. The international journal of biochemistry & cell biology 46 21855646
2011 TRESK: the lone ranger of two-pore domain potassium channels. Molecular and cellular endocrinology 43 22115960
2008 Lamotrigine inhibits TRESK regulated by G-protein coupled receptor agonists. Biochemical and biophysical research communications 43 18190784
2013 Intrathecal TRESK gene recombinant adenovirus attenuates spared nerve injury-induced neuropathic pain in rats. Neuroreport 41 23370493
2005 Species-specific differences in response to anesthetics and other modulators by the K2P channel TRESK. Anesthesia and analgesia 41 16192517
2009 Regional expression of the anesthetic-activated potassium channel TRESK in the rat nervous system. Neuroscience letters 39 19716403
2008 Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK regulation. The Journal of biological chemistry 38 18397886
2005 Zinc and mercuric ions distinguish TRESK from the other two-pore-domain K+ channels. Molecular pharmacology 37 16354767
2010 Discrete change in volatile anesthetic sensitivity in mice with inactivated tandem pore potassium ion channel TRESK. Anesthesiology 33 21042202
2020 TRESK background K+ channel deletion selectively uncovers enhanced mechanical and cold sensitivity. The Journal of physiology 32 31919847
2018 Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis. Science signaling 32 30327410
2014 Properties, regulation, pharmacology, and functions of the K₂p channel, TRESK. Pflugers Archiv : European journal of physiology 32 25366493
2008 TRESK-like potassium channels in leukemic T cells. Pflugers Archiv : European journal of physiology 31 18506476
2013 Cloxyquin (5-chloroquinolin-8-ol) is an activator of the two-pore domain potassium channel TRESK. Biochemical and biophysical research communications 28 24383077
2010 TRESK background K(+) channel is inhibited by phosphorylation via two distinct pathways. The Journal of biological chemistry 27 20215114
2013 Modulation of TRESK background K+ channel by membrane stretch. PloS one 26 23691227
2012 TRESK gene recombinant adenovirus vector inhibits capsaicin-mediated substance P release from cultured rat dorsal root ganglion neurons. Molecular medicine reports 26 22307830
2019 The Role of TRESK in Discrete Sensory Neuron Populations and Somatosensory Processing. Frontiers in molecular neuroscience 25 31379497
2013 Functional characterization of zebrafish K2P18.1 (TRESK) two-pore-domain K+ channels. Naunyn-Schmiedeberg's archives of pharmacology 23 24311292
2008 Roles of TRESK, a novel two-pore domain K+ channel, in pain pathway and general anesthesia. Neuroscience bulletin 23 18500390
2015 Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling. Scientific reports 22 26224542
2014 Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. Journal of neurophysiology 22 24805079
2017 Selective and state-dependent activation of TRESK (K2P 18.1) background potassium channel by cloxyquin. British journal of pharmacology 21 28419410
2014 Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18. Drug design, development and therapy 21 24899801
2011 TRESK background K(+) channel is inhibited by PAR-1/MARK microtubule affinity-regulating kinases in Xenopus oocytes. PloS one 21 22145024
2009 TRESK channel as a potential target to treat T-cell mediated immune dysfunction. Biochemical and biophysical research communications 20 19852929
2016 TRESK contributes to pain threshold changes by mediating apoptosis via MAPK pathway in the spinal cord. Neuroscience 19 27789381
2020 TRESK and TREK-2 two-pore-domain potassium channel subunits form functional heterodimers in primary somatosensory neurons. The Journal of biological chemistry 17 32641496
2017 Reversal of TRESK Downregulation Alleviates Neuropathic Pain by Inhibiting Activation of Gliocytes in the Spinal Cord. Neurochemical research 17 28160200
2014 The LQLP calcineurin docking site is a major determinant of the calcium-dependent activation of human TRESK background K+ channel. The Journal of biological chemistry 17 25202008
2020 Analysis of Genetic Variants in SCN1A, SCN2A, KCNK18, TRPA1 and STX1A as a Possible Marker of Migraine. Current genomics 16 33071616
2009 N-linked glycosylation determines cell surface expression of two-pore-domain K+ channel TRESK. Biochemical and biophysical research communications 16 20006580
2022 The Special One: Architecture, Physiology and Pharmacology of the TRESK Channel. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 13 36426390
2014 KCNK18 (TRESK) genetic variants in Italian patients with migraine. Headache 13 25324165
2018 Verapamil Inhibits TRESK (K2P18.1) Current in Trigeminal Ganglion Neurons Independently of the Blockade of Ca2+ Influx. International journal of molecular sciences 12 29973548
2012 Identification of blocker binding site in mouse TRESK by molecular modeling and mutational studies. Biochimica et biophysica acta 12 23200789
2019 TRESK alleviates trigeminal neuralgia induced by infraorbital nerve chronic constriction injury in rats. Molecular pain 11 31558093
2024 Sodium butyrate restored TRESK current controlling neuronal hyperexcitability in a mouse model of oxaliplatin-induced peripheral neuropathic pain. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 10 39542827
2021 TRESK background potassium channel modifies the TRPV1-mediated nociceptor excitability in sensory neurons. Cephalalgia : an international journal of headache 10 33525904
2019 Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel. Molecular pharmacology 10 30979812
2014 Tubulin binds to the cytoplasmic loop of TRESK background K⁺ channel in vitro. PloS one 10 24830385
2021 TRESK Regulates Gm11874 to Induce Apoptosis of Spinal Cord Neurons via ATP5i Mediated Oxidative Stress and DNA Damage. Neurochemical research 9 33973102
2021 Contribution of TRESK two-pore domain potassium channel to bone cancer-induced spontaneous pain and evoked cutaneous pain in rats. Molecular pain 9 34102915
2020 Altered functional properties of a missense variant in the TRESK K+ channel (KCNK18) associated with migraine and intellectual disability. Pflugers Archiv : European journal of physiology 9 32394190
2019 High-fat diet-induced vagal afferent dysfunction via upregulation of 2-pore domain potassium TRESK channel. JCI insight 9 31484832
2018 Anionic Phospholipids Bind to and Modulate the Activity of Human TRESK Background K+ Channel. Molecular neurobiology 9 30039335
2016 Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K2P18.1. Bioorganic & medicinal chemistry letters 9 27641472
2013 Analysis of 3 common polymorphisms in the KCNK18 gene in an Australian Migraine case-control cohort. Gene 9 23911303
2025 TRESK background potassium channel regulates MrgprA3 + pruriceptor excitability, acute and chronic itch. Pain 8 40062712
2019 TRESK (K2P18.1) Background Potassium Channel Is Activated by Novel-Type Protein Kinase C via Dephosphorylation. Molecular pharmacology 8 30992311
2013 TRESK potassium channel in human T lymphoblasts. Biochemical and biophysical research communications 8 23541583
2020 Upregulation of TRESK Channels Contributes to Motor and Sensory Recovery after Spinal Cord Injury. International journal of molecular sciences 7 33256222
2019 Changes in the expression of the potassium channels TASK1, TASK3 and TRESK in a rat model of oral squamous cell carcinoma and their relation to malignancy. Archives of oral biology 7 30818127
2016 Increased Activation of the TRESK K+ Mediates Vago-Vagal Reflex Malfunction in Diabetic Rats. Gastroenterology 7 27475306
2021 KCNK18 Biallelic Variants Associated with Intellectual Disability and Neurodevelopmental Disorders Alter TRESK Channel Activity. International journal of molecular sciences 5 34199759
2024 TRESK channel activation ameliorates migraine-like pain via modulation of CGRP release from the trigeminovascular system and meningeal mast cells in experimental migraine models. Life sciences 3 39362587
2021 Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092. Biochemistry and biophysics reports 3 34041373
2024 The Ubiquitin Ligase Adaptor NDFIP1 Interacts with TRESK and Negatively Regulates the Background K+ Current. International journal of molecular sciences 2 39201565
2026 Strain-specific metabolomic and inflammatory profiles in guinea pigs after LPS-induced inflammation: Comparative analysis of Dunkin-Hartley and Trik strains. Respiratory physiology & neurobiology 0 41617117
2023 Critical contribution of the intracellular C-terminal region to TRESK channel activity is revealed by the epithelial Na+ current ratio method. The Journal of biological chemistry 0 37084812

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