Affinage

KCNK10

Potassium channel subfamily K member 10 · UniProt P57789

Length
538 aa
Mass
59.8 kDa
Annotated
2026-06-10
55 papers in source corpus 29 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNK10 (TREK-2/K2P10.1) is a polymodal two-pore-domain background K+ channel that sets neuronal resting membrane potential and is gated by a broad range of physical and chemical stimuli (PMID:10880510, PMID:10747911). It is activated by membrane stretch, polyunsaturated fatty acids, lysophospholipids, intracellular acidification, and volatile anesthetics, and is outwardly rectifying (PMID:10880510, PMID:10747911); the proximal C-terminal residues E332/K330 are required for activation by acidic intracellular pH (PMID:28988317), and stretch shifts the channel from a 'down' to an 'up' state without altering its strict K+ selectivity (PMID:28377596, PMID:28723241). Thermosensitivity (≈20-fold current increase from 24°C to 42°C) is separable from C-terminus-dependent chemical gating and maps to a C-terminal temperature-responsive element (PMID:15677687). The channel is tonically inhibited by PI(4,5)P2 maintained by intracellular ATP and PI kinase, with sustained Gq signaling producing a biphasic activate-then-inhibit response as PIP2 is hydrolyzed (PMID:19439530, PMID:27283411). Inhibitory inputs converge on phosphorylation: PKC phosphorylates S326/S359 downstream of Gq-coupled M3 receptors, and PKA phosphorylates a C-terminal serine downstream of cAMP, both reducing activity and altering single-channel gating (PMID:11897838, PMID:16672694, PMID:17540699); conversely, disinhibition of tonic PKA suppression downstream of Gi-coupled GABA(B) and α2A-adrenergic receptors activates the channel and depresses neuronal excitability (PMID:19640481, PMID:19244246). Single-channel conductance is determined by N-terminus length through alternative translation initiation, yielding small (~52 pS) and large (~185–224 pS) phenotypes (PMID:18845607). TREK-2 forms functional heterodimers with TREK-1 and with TRESK, generating channels of intermediate biophysical and pharmacological properties in native sensory neurons (PMID:27129242, PMID:32641496). Functionally, TREK-2 sets the resting potential of IB4+ C-fiber nociceptors and limits spontaneous pain, and knockout mice show altered thermosensation and increased mechanical and osmotic pain (PMID:24453337, PMID:25239074). High-resolution nanobody-bound structures have defined extracellular and Cap-domain sites for channel modulation (PMID:38755204).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Establishing what KCNK10 does at all: identified TREK-2 as a polymodal mechanosensitive background K+ channel responsive to fatty acids, acid, stretch and anesthetics, defining its core biophysical identity.

    Evidence Heterologous expression with whole-cell and single-channel patch clamp

    PMID:10747911 PMID:10880510

    Open questions at the time
    • Structural basis of stimulus sensing not resolved
    • Native cellular role not yet established
  2. 2002 High

    Resolved how cAMP suppresses the channel by mapping PKA-dependent inhibition to a defined C-terminal serine and identifying tissue-specific splice isoforms.

    Evidence cDNA cloning, HEK293 expression, site-directed mutagenesis (S364A), whole-cell patch clamp

    PMID:11897838

    Open questions at the time
    • Upstream receptors driving cAMP regulation not yet identified
    • Isoform-specific physiology unknown
  3. 2005 High

    Separated heat gating from chemical gating, showing thermosensitivity is mechanistically distinct from the C-terminus-dependent fatty-acid/proton response.

    Evidence Temperature ramps and TREK-2/TASK-3 C-terminal chimeras in COS-7 cells and native neurons

    PMID:15677687

    Open questions at the time
    • Molecular element conferring heat sensitivity not localized in this study
  4. 2006 High

    Defined the mechanism of Gq-receptor inhibition, showing PKC phosphorylation at S326/S359 rather than PIP2 depletion, Ca2+, or DAG mediates acute muscarinic inhibition.

    Evidence M3 receptor co-expression, site-directed mutagenesis, pharmacological controls, patch clamp

    PMID:16672694

    Open questions at the time
    • Interplay with PIP2 regulation under sustained signaling not fully resolved here
  5. 2007 High

    Connected phosphorylation to single-channel behavior, showing PKA/PKC phosphorylation shifts gating modes and conductance, and added an MLCK-dependent oxidative activation route.

    Evidence Single-channel patch clamp with kinase activators and phosphomimetic mutants; H2O2/MLCK pharmacology in CHO cells

    PMID:17410710 PMID:17540699

    Open questions at the time
    • H2O2/MLCK intermediate not identified at molecular level
    • Physiological context of oxidative activation unclear
  6. 2008 High

    Explained the dual conductance phenotype, showing N-terminus length set by alternative translation initiation controls single-channel conductance, and localized an oxidation-sensitive C-terminal region.

    Evidence Mutagenesis of translation start sites, Western blot, single-channel patch clamp; DTNB chimera mapping (aa 353-383)

    PMID:18845607 PMID:19967058

    Open questions at the time
    • Functional significance of conductance switching in vivo unknown
    • Identity of oxidation-sensitive residues not pinpointed
  7. 2009 High

    Placed TREK-2 in physiological signaling circuits: Gi-coupled GABA(B) and α2A-adrenergic receptors activate it via PKA disinhibition to depress excitability, and intrinsic PIP2 tonically inhibits it.

    Evidence Native entorhinal cortex slice patch clamp with pathway dissection and PKA-site mutagenesis; siRNA and PI-kinase pharmacology in B cells

    PMID:19244246 PMID:19439530 PMID:19640481

    Open questions at the time
    • Behavioral significance of cortical TREK-2 modulation incompletely defined
    • Quantitative coupling of PIP2 to gating not yet resolved
  8. 2014 High

    Established the in vivo nociceptive and thermosensory role, showing TREK-2 sets C-fiber resting potential, limits spontaneous pain, and shapes thermal/mechanical perception.

    Evidence siRNA knockdown and knockout mice with electrophysiology and behavioral pain/thermosensory assays; plus a metabolic role in adipogenesis

    PMID:24453337 PMID:25239074 PMID:25501330

    Open questions at the time
    • Mechanism upstream of adipogenic signaling unresolved (Medium-confidence, single cell type)
    • Relative contribution of TREK-2 vs TREK-1/TRAAK in vivo only partially separated
  9. 2016 High

    Showed combinatorial diversity, demonstrating TREK-2 heterodimerizes with TREK-1 to produce channels of intermediate properties in native DRG neurons, and refined PIP2's dual regulatory mode.

    Evidence Tandem constructs, co-immunoprecipitation, single-channel patch clamp; voltage-sensitive phosphatase and ATP/PI-kinase manipulation across multiple cell types

    PMID:27129242 PMID:27283411

    Open questions at the time
    • Stoichiometry and abundance of native heterodimers unquantified
    • Switch point between PIP2 activation and inhibition not mechanistically defined
  10. 2017 High

    Defined residues and conformational logic of gating: E332/K330 govern acidic-pH activation and PIP2 inhibition, while MD simulations revealed a 'pinched' selectivity filter stabilized in the down state and destabilized by stretch without loss of K+ selectivity.

    Evidence Inside-out patch clamp with mutagenesis; 195-µs all-atom MD with Markov modeling; reversal-potential selectivity measurements under stretch

    PMID:28377596 PMID:28723241 PMID:28988317

    Open questions at the time
    • Pinched-filter state lacks direct experimental confirmation (computational)
    • How a single residue couples two distinct regulatory inputs unresolved
  11. 2020 High

    Extended heteromeric diversity to TRESK, showing TRESK/TREK-2 heterodimers in sensory neurons combine calcineurin-dependent regulation with TREK-2-selective pharmacology.

    Evidence Covalently linked tandem construct, single-channel patch clamp, pharmacological fingerprinting, native DRG/trigeminal recordings

    PMID:32641496

    Open questions at the time
    • Physiological prevalence of TRESK/TREK-2 heterodimers unquantified
  12. 2024 High

    Delivered direct structural mechanism, with nanobody-bound X-ray and cryo-EM structures defining extracellular and Cap-domain sites for activation and inhibition, and revealed acyl-chain-dependent lipid selectivity.

    Evidence Camelid nanobody generation, crystallography, cryo-EM, structure-guided engineering; native mass spectrometry of lipid binding

    PMID:38755204 PMID:38843438

    Open questions at the time
    • Therapeutic applicability of nanobody modulators untested in vivo
    • Lipid-affinity to gating link (Medium-confidence) lacks mutagenesis
  13. 2025 Medium

    Refined activating and trafficking inputs: calcineurin activates TREK-2 in a calcium- and AKAP5-anchored manner, the C-terminal temperature-responsive element couples thermosensitivity to MAP2/microtubules and PKA, and β-COP suppresses surface expression.

    Evidence Oocyte expression with calcineurin pharmacology and AKAP5 co-expression; C-terminal chimeras with microtubule/PKA pharmacology (preprint); co-IP and surface biotinylation with C-terminal mutagenesis

    PMID:37296621 PMID:41457157

    Open questions at the time
    • Calcineurin mutagenesis primarily validated for TREK-1, not TREK-2
    • Thermosensitivity element findings remain a preprint
    • β-COP trafficking effect not confirmed in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (mechanical, lipid, phosphorylation, temperature, trafficking) are integrated quantitatively at the gating machinery in native neurons, and whether KCNK10 variants cause human disease, remain open.
  • No human Mendelian disease link established in the timeline
  • No unified gating model integrating all polymodal inputs
  • In vivo significance of conductance/isoform switching unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140299 molecular sensor activity 4 GO:0005215 transporter activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4
Partners
AKAP5KCNK18KCNK2
Complex memberships
TREK-1/TREK-2 heterodimerTRESK/TREK-2 heterodimer

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TREK-2 (KCNK10) is a mechanosensitive, outwardly rectifying background K+ channel with single-channel conductance of ~100 pS, activated by polyunsaturated fatty acids (arachidonic, docosahexaenoic, linoleic acids), lysophosphatidylcholine, intracellular acidification, membrane stretch, and volatile anesthetics (chloroform, halothane, isoflurane). Channel activity is inhibited by intracellular cAMP. Heterologous expression in transfected cells; whole-cell and single-channel patch clamp electrophysiology The Journal of biological chemistry High 10747911 10880510
2000 TREK-2 is activated by membrane stretch (10-fold increase at -40 mmHg), arachidonic acid, other unsaturated free fatty acids, and acidic pH; single-channel conductances are 110 pS at -40 mV and 68 pS at +40 mV in symmetrical 150 mM KCl. Heterologous expression in COS-7 cells; cell-attached and excised patch clamp electrophysiology The Journal of biological chemistry High 10747911
2002 Two alternatively spliced isoforms of TREK-2 (TREK-2b from kidney/pancreas; TREK-2c from brain) were identified. A PKA phosphorylation site mutation at position S364A in TREK-2c abolished forskolin-mediated current inhibition, demonstrating that PKA-dependent phosphorylation at S364 mediates cAMP/PKA inhibition of TREK-2. cDNA cloning from human cDNA libraries; HEK293 expression; whole-cell patch clamp; site-directed mutagenesis The Journal of physiology High 11897838
2005 TREK-2 is a thermosensitive channel: whole-cell currents increase ~20-fold as temperature rises from 24°C to 42°C (threshold ~25°C) in COS-7 cells. Replacement of the TREK-2 C-terminus with that of TASK-3 abolished sensitivity to fatty acids and protons but did not abolish heat activation, indicating that C-terminus-dependent and heat-dependent activation mechanisms are separable. Transfected COS-7 cells and native neurons; whole-cell and cell-attached patch clamp; temperature ramp; C-terminal chimera constructs The Journal of physiology High 15677687
2006 Inhibition of TREK-2 by Gq-coupled M3 muscarinic receptor activation (acetylcholine) is mediated primarily by PKC-dependent phosphorylation at S326 and S359; mutation of both sites (S326A, S359C) abolished ACh-induced inhibition, while phosphomimetic mutations (S326D, S359D) reduced basal TREK-2 current. PIP2 depletion and direct application of GTP-γS, Ca2+, or DAG did not mediate the inhibition. COS-7 cells co-expressing TREK-2 and M3 receptor; whole-cell and cell-attached/inside-out patch clamp; pharmacological inhibitors; site-directed mutagenesis American journal of physiology. Cell physiology High 16672694
2007 TREK-2 exhibits two primary gating modes producing small (~54 pS, TREK-2S) and large (~202 pS, TREK-2L) conductance phenotypes. Phosphorylation by PKA and PKC (and okadaic acid treatment) shifts TREK-2 gating from these two primary modes to include intermediate conductance levels and reduces channel activity. Phosphomimetic mutations S326D and S359D recapitulate the phosphorylated state with low activity and intermediate conductances. COS-7, HEK293, HeLa cells; Xenopus oocytes; single-channel patch clamp; pharmacological activation of PKA/PKC; site-directed mutagenesis The Journal of physiology High 17540699
2008 The single-channel conductance of TREK-2 is controlled by the length of its N-terminus through alternative translation initiation. The longer isoform (translation from M1) produces the small-conductance (~52 pS) channel, while shorter isoforms (translation from M2 or M3, lacking the distal half of the N-terminus) produce large-conductance (~185–224 pS) channels. Deletion of amino acids 1–66 (but not 1–36) converts the channel to the large-conductance form, localizing the conductance-controlling region to the distal half of the N-terminus. Western blot; site-directed mutagenesis of translation initiation sites; single-channel patch clamp in mammalian cells The Journal of physiology High 18845607
2009 GABA(B) receptor activation inhibits neuronal excitability in the entorhinal cortex by activating TREK-2 K+ channels; this pathway requires Gi protein function and the PKA signaling pathway (disinhibition of PKA-mediated tonic inhibition of TREK-2). Whole-cell patch clamp in entorhinal cortex slices; pharmacological dissection with specific receptor/kinase inhibitors; Morris water maze behavioral assay Neuron High 19640481
2009 Norepinephrine-induced hyperpolarization and depression of neuronal excitability in superficial entorhinal cortex neurons is mediated by α2A adrenergic receptor → Gαi → adenylyl cyclase/PKA pathway activating TREK-2; mutation of the PKA phosphorylation site on TREK-2 abolished norepinephrine's effect. Whole-cell patch clamp in entorhinal cortex slices; pharmacological inhibitors; site-directed mutagenesis of TREK-2 PKA site The Journal of biological chemistry High 19244246
2009 TREK-2 was identified as the large-conductance background K+ channel (LK_bg) in mouse B cells (WEHI-231); siRNA knockdown of TREK-2 reduced background K+ current amplitude. TREK-2 is tonically inhibited by intrinsic PIP2 maintained by intracellular ATP and PI kinase; wortmannin prevented the ATP-dependent inhibition. RT-PCR; immunoblot; single-channel and whole-cell patch clamp; siRNA knockdown; pharmacological PI kinase inhibition American journal of physiology. Cell physiology High 19439530
2007 Hydrogen peroxide selectively increases TREK-2 currents through a mechanism requiring myosin light chain kinase (MLCK) activation, not through direct oxidation of TREK-2 protein; MLCK inhibitors blocked H2O2-induced activation, and H2O2 had no effect in excised inside-out patches, implicating an intracellular signaling intermediate. Whole-cell (perforated and ruptured) and single-channel patch clamp in CHO cells; pharmacological inhibitors; inside-out patches Frontiers in bioscience Medium 17410710
2014 TREK-2 is selectively expressed in IB4-binding C-fiber nociceptors in rat DRG; siRNA knockdown of TREK-2 in culture depolarized these neurons by ~10 mV. In vivo, TREK-2 knockdown increased spontaneous pain (foot lifting) after CFA-induced inflammation, demonstrating that TREK-2 sets the resting membrane potential of C-nociceptors and limits spontaneous pain. Immunohistochemistry; siRNA knockdown; whole-cell patch clamp; in vivo behavioral assay (spontaneous foot lifting) The Journal of neuroscience High 24453337
2014 TREK-2 knockout mice show altered perception of non-aversive warm temperatures (40–46°C) and moderate cool temperatures (20–25°C), and exhibit increased mechanical pain and osmotic pain after PGE2 sensitization; TREK-2 controls C-fiber firing activity in response to temperature changes, demonstrating a role in thermosensation complementary to but distinct from TREK-1 and TRAAK. TREK-2 knockout mice; behavioral thermosensory and nociceptive assays; peripheral C-fiber electrophysiology Pain High 25239074
2015 Ruthenium red (RR) inhibits TREK-2 (IC50 = 0.2 μM) but not TREK-1; aspartate 135 (D135) in the extracellular ion pathway (EIP) of TREK-2 is the target residue. Mutation of the corresponding isoleucine in TREK-1 (I110D) conferred RR sensitivity, confirming D135 as the structural determinant for differential RR sensitivity. Two-electrode voltage clamp in Xenopus oocytes; whole-cell patch clamp in DRG neurons; site-directed mutagenesis British journal of pharmacology High 25409575
2016 TREK-1 and TREK-2 subunits form functional heterodimers when co-expressed; the TREK-1/TREK-2 heterodimer has biophysical and pharmacological properties intermediate between the two homodimers (unique single-channel conductance, intermediate ruthenium red sensitivity) and is inhibited by extracellular acidification and spadin similarly to TREK-1. Heterodimerization was confirmed by co-immunoprecipitation of epitope-tagged subunits and was also detected in native DRG neurons. Tandem-linked construct enforcing heterodimerization; co-immunoprecipitation of epitope-tagged subunits in Xenopus oocytes; single-channel and whole-cell patch clamp; native DRG neuron characterization The Journal of biological chemistry High 27129242
2016 PI(4,5)P2 inhibits TREK-2 through an ATP-dependent mechanism: intracellular ATP maintains PIP2 via PI kinase, and this PIP2 tonically inhibits TREK-2. Wortmannin (PI kinase inhibitor) prevented ATP-dependent inhibition. Sustained PIP2 hydrolysis (via Gq-coupled M3 receptor) first transiently activates then inhibits TREK-2, revealing dual regulatory modes depending on PIP2 concentration. Inside-out and whole-cell patch clamp in HEK293T, COS-7, astrocytes, and WEHI-231 B cells; voltage-sensitive PIP2 phosphatase co-expression; pharmacological inhibitors Pflugers Archiv High 27283411
2017 Molecular dynamics simulations revealed a novel 'pinched' selectivity filter (SF) configuration in TREK-2 that impairs ion conduction and is exclusively stabilized in the compressed ('down') conformation. Stretch activation rapidly destabilizes this pinched state, allosterically linking structural changes in the intracellular helix arrangement to SF gating. 195 μs all-atom unbiased molecular dynamics simulations; Markov state modeling; free-energy barrier calculations based on published TREK-2 crystal structures Scientific reports Medium 28377596
2017 E332 and K330 in the proximal C-terminus of human TREK-2 are critical for activation by acidic intracellular pH; E332A and K330A mutations abolished acidic pHi-induced activation. These same residues are required for ATP-dependent inhibition (via PIP2). E335A partially attenuated pHi sensitivity. Inside-out patch clamp in HEK293T cells expressing WT and mutant human TREK-2; intracellular pH manipulation; intracellular ATP application Pflugers Archiv High 28988317
2017 The stretch-activated structural transition of TREK-2 from 'down' to 'up' state does not alter ionic selectivity; the selectivity filter remains highly selective for K+ over Na+ and other cations (Rb+, Cs+, NH4+) during stretch activation. Electrophysiology with reversal potential measurements under stretch; based on structural data from prior crystal structures Channels (Austin, Tex.) Medium 28723241
2014 KCNK10 (TREK-2) functions as a positive regulator of mitotic clonal expansion (MCE) during early adipocyte differentiation; KCNK10 knockdown suppressed C/EBPβ and C/EBPδ expression and reduced Akt phosphorylation (including insulin-induced Akt phosphorylation), placing KCNK10 upstream of these transcription factors and insulin signaling in the adipogenic program. siRNA knockdown in 3T3-L1 cells; western blot for C/EBPβ, C/EBPδ, Akt phosphorylation; cell proliferation assays during adipocyte differentiation International journal of molecular sciences Medium 25501330
2019 Pranlukast (a CysLT1 antagonist) is a selective small-molecule activator of TREK2 versus TREK1 and TRAAK; mutagenesis studies indicate pranlukast does not bind in the established K2P modulator pocket or the BL-1249 binding site, suggesting a distinct activation mechanism. Thallium flux cell-based assay for screening; whole-cell patch clamp electrophysiology; site-directed mutagenesis of TREK2 Biochemical and biophysical research communications Medium 31564414
2020 TRESK and TREK-2 subunits form functional heterodimers in primary somatosensory (DRG and trigeminal ganglion) neurons. The TRESK/TREK-2 heterodimer has intermediate single-channel conductance versus either homodimer; the TRESK component confers calcineurin-dependent regulation, while the TREK-2 subunit renders the channel sensitive to the TREK-2-selective activator T2A3. Native heterodimeric activity was detected in trigeminal neurons. Covalently linked tandem TRESK/TREK-2 construct; single-channel patch clamp; pharmacological characterization; native DRG/trigeminal ganglion neuron recordings The Journal of biological chemistry High 32641496
2021 β-COP binds to the C-terminus of TREK-2 and reduces its cell surface expression; deletion or point mutations in the C-terminus of TREK-2 prevent β-COP binding and abolish the effect on surface expression. Unlike TREK1, TREK-2 is subject to this β-COP-mediated suppression of surface expression. Co-immunoprecipitation; cell surface biotinylation assay; site-directed mutagenesis of TREK-2 C-terminus; heterologous expression Cells Medium 37296621
2021 Muscimol (GABAAR agonist) directly activates TREK-2 through the channel's N-terminus; the activation was abolished in an N-terminal deletion mutant. GABAAR and GABABR agonists also upregulate TREK-2 mRNA and protein expression in B35 neuroblastic cells. Whole-cell and single-channel patch clamp in B35 cells and HEK293 transfected cells; N-terminal deletion mutant; RT-PCR; western blot International journal of molecular sciences Medium 34502229
2022 GDNF (but not NGF, neurturin, or artemin) upregulates TREK-2 expression in cultured DRG neurons; in vivo continuous GDNF administration restored subcellular distribution of TREK-2 after spinal nerve axotomy and reversed mechanical and cold allodynia, establishing GDNF as an upstream regulator of TREK-2 expression and membrane localization in C-nociceptors. Immunohistochemistry; immunocytochemistry; western blotting; in vivo pharmacological manipulation (GDNF subcutaneous infusion); behavioral allodynia assays Experimental neurology Medium 35907583
2024 Nanobodies against TREK-2 (KCNK10) directly modulate channel activity; X-ray crystallography and cryo-EM structures of nanobody–TREK-2 complexes revealed mechanisms of activation and inhibition via binding to extracellular loops and the Cap domain. A biparatropic inhibitory nanobody with improved potency was designed based on these structures. Camelid nanobody generation; X-ray crystallography; cryo-EM; electrophysiological channel activity assays; structure-guided nanobody engineering Nature communications High 38755204
2024 TREK-2 displays acyl-chain-dependent lipid binding preferences in addition to headgroup selectivity; SAPI(4,5)P2 (stearoyl-arachidonoyl) exhibits higher affinity for TREK-2 than dOPI(4,5)P2 (dioleoyl), and lipid binding affinity correlates with channel activity. Native mass spectrometry; functional activity correlation assays Journal of the American Society for Mass Spectrometry Medium 38843438
2025 Thermosensitivity of TREK-2 requires its C-terminal domain, specifically an 18-amino-acid temperature-responsive element (TRE) that contains both the MAP2 binding domain and a PKA phosphorylation site; pharmacological disruption of microtubule network or loss of MAP2 binding suppressed temperature responses, and PKA activation completely abolished thermosensitivity. TRAAK showed no temperature dependence even with TREK C-terminus substitution experiments in the same study. Chimeric channel constructs with C-terminal exchanges; C-terminal truncation series; pharmacological disruption of microtubule network; PKA activation/inhibition; whole-cell patch clamp; Xenopus oocyte expression bioRxivpreprint Medium
2025 Calcineurin (calcium/calmodulin-dependent protein phosphatase) activates TREK-2 in a calcium-dependent manner; ionomycin-induced calcium increase activates TREK-2 (in the presence of ML-335 activator), and this effect is blocked by calcineurin inhibitors cyclosporin A and FK506. AKAP5 (AKAP79/AKAP150) enhances calcium-dependent TREK activation by anchoring calcineurin near the channel. Xenopus oocyte expression; ionomycin and IP3 injection; pharmacological calcineurin inhibitors; constitutively active calcineurin co-expression; site-directed mutagenesis of phosphorylation sites on TREK-1 (validated for TREK-2 by ionomycin experiment) Scientific reports Medium 41457157
2008 The TREK-2 C-terminus region between amino acids 353 and 383 is the target site for oxidation-mediated inhibition by DTNB; chimeras replacing TREK-2 sequence beyond position 383 with TASK3 C-terminus retained DTNB sensitivity, while a chimera truncated at position 353 did not. Inside-out patch clamp in COS-7 cells; TREK2/TASK3 chimeric constructs; application of oxidizing (DTNB) and reducing (DTT) agents The Korean journal of physiology & pharmacology Medium 19967058

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. The Journal of biological chemistry 269 10880510
2000 TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family. The Journal of biological chemistry 225 10747911
2005 Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. The Journal of physiology 205 15677687
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
2014 Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception. Pain 115 25239074
2009 GABA(B) receptor activation inhibits neuronal excitability and spatial learning in the entorhinal cortex by activating TREK-2 K+ channels. Neuron 102 19640481
2014 TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 92 24453337
2002 Expression pattern and functional characteristics of two novel splice variants of the two-pore-domain potassium channel TREK-2. The Journal of physiology 85 11897838
2009 Noradrenergic depression of neuronal excitability in the entorhinal cortex via activation of TREK-2 K+ channels. The Journal of biological chemistry 62 19244246
2008 Control of the single channel conductance of K2P10.1 (TREK-2) by the amino-terminus: role of alternative translation initiation. The Journal of physiology 58 18845607
2006 Mechanism of inhibition of TREK-2 (K2P10.1) by the Gq-coupled M3 muscarinic receptor. American journal of physiology. Cell physiology 55 16672694
2002 Functional expression of TREK-2 K+ channel in cultured rat brain astrocytes. Brain research 45 11897089
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
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
2016 Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits. The Journal of biological chemistry 38 27129242
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
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
2009 Ischemia Increases TREK-2 Channel Expression in Astrocytes: Relevance to Glutamate Clearance. The open neuroscience journal 32 19890471
2007 Properties of single two-pore domain TREK-2 channels expressed in mammalian cells. The Journal of physiology 30 17540699
2011 Identification and functional characterization of zebrafish K(2P)10.1 (TREK2) two-pore-domain K(+) channels. Biochimica et biophysica acta 28 21963410
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
2009 Identification of the large-conductance background K+ channel in mouse B cells as TREK-2. American journal of physiology. Cell physiology 24 19439530
2016 miRNA-187-3p-Mediated Regulation of the KCNK10/TREK-2 Potassium Channel in a Rat Epilepsy Model. ACS chemical neuroscience 23 27609046
2004 Functional expression of TREK-2 in insulin-secreting MIN6 cells. Biochemical and biophysical research communications 22 15351740
2011 Baicalein and wogonin are activators of rat TREK-2 two-pore domain K+ channel. Acta physiologica (Oxford, England) 20 21306568
2017 Activation of TREK-1, but Not TREK-2, Channel by Mood Stabilizers. International journal of molecular sciences 19 29156592
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
2019 Pranlukast is a novel small molecule activator of the two-pore domain potassium channel TREK2. Biochemical and biophysical research communications 17 31564414
2018 TREK-2 Mediates the Neuroprotective Effect of Isoflurane Preconditioning Against Acute Cerebral Ischemia in the Rat. Rejuvenation research 15 30412001
2017 Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter. Scientific reports 15 28377596
2007 Recent advance and possible future in TREK-2: a two-pore potassium channel may involved in the process of NPP, brain ischemia and memory impairment. Medical hypotheses 15 17689202
2014 KCNK10, a tandem pore domain potassium channel, is a regulator of mitotic clonal expansion during the early stage of adipocyte differentiation. International journal of molecular sciences 14 25501330
2016 Inhibition of TREK-2 K(+) channels by PI(4,5)P2: an intrinsic mode of regulation by intracellular ATP via phosphatidylinositol kinase. Pflugers Archiv : European journal of physiology 13 27283411
2015 Up-regulation of TREK-2 potassium channels in cultured astrocytes requires de novo protein synthesis: relevance to localization of TREK-2 channels in astrocytes after transient cerebral ischemia. PloS one 12 25886567
2007 Hydrogen peroxide selectively increases TREK-2 currents via myosin light chain kinases. Frontiers in bioscience : a journal and virtual library 12 17127410
2024 Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation. Nature communications 10 38755204
2013 The TREK2 Channel Is Involved in the Proliferation of 253J Cell, a Human Bladder Carcinoma Cell. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 10 24381500
2017 Identification of critical amino acids in the proximal C-terminal of TREK-2 K+ channel for activation by acidic pHi and ATP-dependent inhibition. Pflugers Archiv : European journal of physiology 9 28988317
2022 Glial-derived neurotrophic factor regulates the expression of TREK2 in rat primary sensory neurons leading to attenuation of axotomy-induced neuropathic pain. Experimental neurology 8 35907583
2021 The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels. Frontiers in pharmacology 6 34267666
2017 Kinetic properties and adrenergic control of TREK-2-like channels in rat medial prefrontal cortex (mPFC) pyramidal neurons. Brain research 6 28438532
2016 Intersubunit Concerted Cooperative and cis-Type Mechanisms Modulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2. Frontiers in cellular neuroscience 6 27242438
2011 Identification and characterization of alternative splice variants of the mouse Trek2/Kcnk10 gene. Neuroscience 6 21821104
2021 Effects of GABAB receptor activation on excitability of IB4-positive maxillary trigeminal ganglion neurons: Possible involvement of TREK2 activation. Molecular pain 4 34461754
2020 Dual regulatory effects of PI(4,5)P2 on TREK-2 K+ channel through antagonizing interaction between the alkaline residues (K330 and R355-357) in the cytosolic C-terminal helix. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 4 33093276
2017 The effects of stretch activation on ionic selectivity of the TREK-2 K2P K+ channel. Channels (Austin, Tex.) 4 28723241
2016 Propofol postsynaptically suppresses stellate neuron excitability in the entorhinal cortex by influencing the HCN and TREK-2 channels. Neuroscience letters 4 26971702
2015 The isoforms generated by alternative translation initiation adopt similar conformation in the selectivity filter in TREK-2. Journal of physiology and biochemistry 4 26271386
2023 β-COP Suppresses the Surface Expression of the TREK2. Cells 3 37296621
2008 The Inhibition of TREK2 Channel by an Oxidizing Agent, 5,5'-dithio-bis (2-nitrobenzoic acid), via Interaction with the C-terminus Distal to the 353rd Amino Acid. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 3 19967058
2024 TREK2 Lipid Binding Preferences Revealed by Native Mass Spectrometry. Journal of the American Society for Mass Spectrometry 2 38843438
2021 Higher expression of KCNK10 (TREK-2) K+ channels and their functional upregulation by lipopolysaccharide treatment in mouse peritoneal B1a cells. Pflugers Archiv : European journal of physiology 2 33586023
2021 Muscimol Directly Activates the TREK-2 Channel Expressed in GABAergic Neurons through Its N-Terminus. International journal of molecular sciences 2 34502229
2021 Activity of TREK-2-like Channels in the Pyramidal Neurons of Rat Medial Prefrontal Cortex Depends on Cytoplasmic Calcium. Biology 2 34827112
2025 Calcium-dependent activation of TREK-1 and TREK-2 background potassium channels by calcineurin. Scientific reports 0 41457157

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