{"gene":"KCNK10","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"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.","method":"Heterologous expression in transfected cells; whole-cell and single-channel patch clamp electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological characterization with multiple stimuli, independently replicated in a second paper (PMID:10747911) in the same year","pmids":["10880510","10747911"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Heterologous expression in COS-7 cells; cell-attached and excised patch clamp electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct single-channel electrophysiology with multiple orthogonal stimuli, replicated by PMID:10880510","pmids":["10747911"],"is_preprint":false},{"year":2002,"finding":"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.","method":"cDNA cloning from human cDNA libraries; HEK293 expression; whole-cell patch clamp; site-directed mutagenesis","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis combined with electrophysiology, two splice isoforms functionally characterized","pmids":["11897838"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Transfected COS-7 cells and native neurons; whole-cell and cell-attached patch clamp; temperature ramp; C-terminal chimera constructs","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology with chimera mutagenesis in multiple cell types including native neurons","pmids":["15677687"],"is_preprint":false},{"year":2006,"finding":"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.","method":"COS-7 cells co-expressing TREK-2 and M3 receptor; whole-cell and cell-attached/inside-out patch clamp; pharmacological inhibitors; site-directed mutagenesis","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with electrophysiology, multiple pharmacological controls ruling out alternative pathways","pmids":["16672694"],"is_preprint":false},{"year":2007,"finding":"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.","method":"COS-7, HEK293, HeLa cells; Xenopus oocytes; single-channel patch clamp; pharmacological activation of PKA/PKC; site-directed mutagenesis","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-channel electrophysiology with mutagenesis across multiple cell lines and native neurons","pmids":["17540699"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Western blot; site-directed mutagenesis of translation initiation sites; single-channel patch clamp in mammalian cells","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with biochemical and electrophysiological validation across multiple constructs","pmids":["18845607"],"is_preprint":false},{"year":2009,"finding":"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).","method":"Whole-cell patch clamp in entorhinal cortex slices; pharmacological dissection with specific receptor/kinase inhibitors; Morris water maze behavioral assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiology in native neurons with pharmacological pathway dissection, behavioral outcome linked to TREK-2 activation","pmids":["19640481"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Whole-cell patch clamp in entorhinal cortex slices; pharmacological inhibitors; site-directed mutagenesis of TREK-2 PKA site","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus electrophysiology in native neurons, pathway fully dissected pharmacologically","pmids":["19244246"],"is_preprint":false},{"year":2009,"finding":"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.","method":"RT-PCR; immunoblot; single-channel and whole-cell patch clamp; siRNA knockdown; pharmacological PI kinase inhibition","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown confirming molecular identity, pharmacological pathway dissection, multiple electrophysiological configurations","pmids":["19439530"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Whole-cell (perforated and ruptured) and single-channel patch clamp in CHO cells; pharmacological inhibitors; inside-out patches","journal":"Frontiers in bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological dissection in single lab, single cell type, no mutagenesis confirmation","pmids":["17410710"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Immunohistochemistry; siRNA knockdown; whole-cell patch clamp; in vivo behavioral assay (spontaneous foot lifting)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with defined electrophysiological and behavioral phenotypes, corroborated by in vivo expression-function correlation","pmids":["24453337"],"is_preprint":false},{"year":2014,"finding":"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.","method":"TREK-2 knockout mice; behavioral thermosensory and nociceptive assays; peripheral C-fiber electrophysiology","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined behavioral and electrophysiological phenotypes","pmids":["25239074"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Two-electrode voltage clamp in Xenopus oocytes; whole-cell patch clamp in DRG neurons; site-directed mutagenesis","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with electrophysiology confirming structural basis of pharmacological selectivity, validated in native DRG neurons","pmids":["25409575"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — tandem construct plus reciprocal co-IP plus electrophysiology, validated in native tissue","pmids":["27129242"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"Pflugers Archiv","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types, multiple patch configurations, co-expression of voltage-sensitive phosphatase, confirmed endogenous regulation","pmids":["27283411"],"is_preprint":false},{"year":2017,"finding":"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.","method":"195 μs all-atom unbiased molecular dynamics simulations; Markov state modeling; free-energy barrier calculations based on published TREK-2 crystal structures","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 (computational) / Weak — extensive MD simulation with Markov modeling, but no direct experimental validation of the pinched state in the abstract","pmids":["28377596"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Inside-out patch clamp in HEK293T cells expressing WT and mutant human TREK-2; intracellular pH manipulation; intracellular ATP application","journal":"Pflugers Archiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with electrophysiology defining specific residues for two regulatory mechanisms","pmids":["28988317"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Electrophysiology with reversal potential measurements under stretch; based on structural data from prior crystal structures","journal":"Channels (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — electrophysiological selectivity measurements in single lab, single method","pmids":["28723241"],"is_preprint":false},{"year":2014,"finding":"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.","method":"siRNA knockdown in 3T3-L1 cells; western blot for C/EBPβ, C/EBPδ, Akt phosphorylation; cell proliferation assays during adipocyte differentiation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA knockdown with defined molecular phenotype in single lab, single cell type","pmids":["25501330"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Thallium flux cell-based assay for screening; whole-cell patch clamp electrophysiology; site-directed mutagenesis of TREK2","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological characterization with mutagenesis, but binding site not positively identified; single lab","pmids":["31564414"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Covalently linked tandem TRESK/TREK-2 construct; single-channel patch clamp; pharmacological characterization; native DRG/trigeminal ganglion neuron recordings","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — tandem construct enforcing subunit stoichiometry plus pharmacological fingerprinting plus native cell validation","pmids":["32641496"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation; cell surface biotinylation assay; site-directed mutagenesis of TREK-2 C-terminus; heterologous expression","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP with mutagenesis confirming binding site, single lab, no in vivo confirmation","pmids":["37296621"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Whole-cell and single-channel patch clamp in B35 cells and HEK293 transfected cells; N-terminal deletion mutant; RT-PCR; western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mutagenesis with electrophysiology, but single lab and limited mechanistic detail in abstract","pmids":["34502229"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Immunohistochemistry; immunocytochemistry; western blotting; in vivo pharmacological manipulation (GDNF subcutaneous infusion); behavioral allodynia assays","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo and in vitro pharmacological manipulation with functional outcomes, single lab","pmids":["35907583"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Camelid nanobody generation; X-ray crystallography; cryo-EM; electrophysiological channel activity assays; structure-guided nanobody engineering","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution structures (X-ray and cryo-EM) with functional validation and structure-guided design, multiple orthogonal methods","pmids":["38755204"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Native mass spectrometry; functional activity correlation assays","journal":"Journal of the American Society for Mass Spectrometry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — native MS with functional correlation, single lab, no mutagenesis","pmids":["38843438"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — preprint; multiple constructs and pharmacological tools but not yet peer-reviewed; single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"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.","method":"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)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological and genetic dissection in oocytes, TREK-2 activation by ionomycin confirmed but mechanistic detail (mutagenesis) primarily shown for TREK-1; single lab","pmids":["41457157"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Inside-out patch clamp in COS-7 cells; TREK2/TASK3 chimeric constructs; application of oxidizing (DTNB) and reducing (DTT) agents","journal":"The Korean journal of physiology & pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — chimera mutagenesis with electrophysiology, single lab, narrow focus","pmids":["19967058"],"is_preprint":false}],"current_model":"TREK-2 (KCNK10/K2P10.1) is a polymodal two-pore domain background K+ channel that is activated by membrane stretch, polyunsaturated fatty acids, intracellular acidification (via E332 in the proximal C-terminus), heat (via a C-terminal temperature-responsive element requiring the microtubule/MAP2 network), volatile anesthetics, calcineurin (calcium-dependent, anchored by AKAP5), and disinhibition of PKA-mediated tonic suppression (downstream of Gi-coupled receptors); it is tonically inhibited by PIP2 maintained through intracellular ATP/PI kinase, and acutely inhibited by PKC-mediated phosphorylation at S326/S359 (downstream of Gq-coupled receptors) and by β-COP-mediated reduction of surface expression; alternative translation initiation from three N-terminal methionines produces isoforms whose N-terminus length controls single-channel conductance (small ~52 pS vs large ~220 pS), while the selectivity filter remains stable and K+-selective during stretch activation; TREK-2 can form functional heterodimers with TREK-1 or TRESK, expanding the diversity of background K+ conductances in native neurons including DRG nociceptors where it hyperpolarizes IB4+ C-fibers and limits spontaneous pain."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["10880510","10747911"],"confidence":"High","gaps":["Structural basis of stimulus sensing not resolved","Native cellular role not yet established"]},{"year":2002,"claim":"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","pmids":["11897838"],"confidence":"High","gaps":["Upstream receptors driving cAMP regulation not yet identified","Isoform-specific physiology unknown"]},{"year":2005,"claim":"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","pmids":["15677687"],"confidence":"High","gaps":["Molecular element conferring heat sensitivity not localized in this study"]},{"year":2006,"claim":"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","pmids":["16672694"],"confidence":"High","gaps":["Interplay with PIP2 regulation under sustained signaling not fully resolved here"]},{"year":2007,"claim":"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","pmids":["17540699","17410710"],"confidence":"High","gaps":["H2O2/MLCK intermediate not identified at molecular level","Physiological context of oxidative activation unclear"]},{"year":2008,"claim":"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)","pmids":["18845607","19967058"],"confidence":"High","gaps":["Functional significance of conductance switching in vivo unknown","Identity of oxidation-sensitive residues not pinpointed"]},{"year":2009,"claim":"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","pmids":["19640481","19244246","19439530"],"confidence":"High","gaps":["Behavioral significance of cortical TREK-2 modulation incompletely defined","Quantitative coupling of PIP2 to gating not yet resolved"]},{"year":2014,"claim":"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","pmids":["24453337","25239074","25501330"],"confidence":"High","gaps":["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"]},{"year":2016,"claim":"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","pmids":["27129242","27283411"],"confidence":"High","gaps":["Stoichiometry and abundance of native heterodimers unquantified","Switch point between PIP2 activation and inhibition not mechanistically defined"]},{"year":2017,"claim":"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","pmids":["28988317","28377596","28723241"],"confidence":"High","gaps":["Pinched-filter state lacks direct experimental confirmation (computational)","How a single residue couples two distinct regulatory inputs unresolved"]},{"year":2020,"claim":"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","pmids":["32641496"],"confidence":"High","gaps":["Physiological prevalence of TRESK/TREK-2 heterodimers unquantified"]},{"year":2024,"claim":"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","pmids":["38755204","38843438"],"confidence":"High","gaps":["Therapeutic applicability of nanobody modulators untested in vivo","Lipid-affinity to gating link (Medium-confidence) lacks mutagenesis"]},{"year":2025,"claim":"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","pmids":["41457157","37296621"],"confidence":"Medium","gaps":["Calcineurin mutagenesis primarily validated for TREK-1, not TREK-2","Thermosensitivity element findings remain a preprint","β-COP trafficking effect not confirmed in vivo"]},{"year":null,"claim":"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.","evidence":"Not addressed by the available corpus","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,1,3,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[15,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,22]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,8,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,8,15]}],"complexes":["TREK-1/TREK-2 heterodimer","TRESK/TREK-2 heterodimer"],"partners":["KCNK2","KCNK18","AKAP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P57789","full_name":"Potassium channel subfamily K member 10","aliases":["Outward rectifying potassium channel protein TREK-2","TREK-2 K(+) channel subunit"],"length_aa":538,"mass_kda":59.8,"function":"K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. 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Channels","date":"2025-01-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.08.631886","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.07.622439","title":"Thermosensitivity of TREK K2P channels is controlled by a PKA switch and depends on the microtubular network","date":"2024-11-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.07.622439","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33407,"output_tokens":7746,"usd":0.108205,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17274,"output_tokens":4546,"usd":0.10001,"stage2_stop_reason":"end_turn"},"total_usd":0.208215,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression in transfected cells; whole-cell and single-channel patch clamp electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological characterization with multiple stimuli, independently replicated in a second paper (PMID:10747911) in the same year\",\n      \"pmids\": [\"10880510\", \"10747911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression in COS-7 cells; cell-attached and excised patch clamp electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct single-channel electrophysiology with multiple orthogonal stimuli, replicated by PMID:10880510\",\n      \"pmids\": [\"10747911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA cloning from human cDNA libraries; HEK293 expression; whole-cell patch clamp; site-directed mutagenesis\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis combined with electrophysiology, two splice isoforms functionally characterized\",\n      \"pmids\": [\"11897838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Transfected COS-7 cells and native neurons; whole-cell and cell-attached patch clamp; temperature ramp; C-terminal chimera constructs\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology with chimera mutagenesis in multiple cell types including native neurons\",\n      \"pmids\": [\"15677687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"COS-7 cells co-expressing TREK-2 and M3 receptor; whole-cell and cell-attached/inside-out patch clamp; pharmacological inhibitors; site-directed mutagenesis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with electrophysiology, multiple pharmacological controls ruling out alternative pathways\",\n      \"pmids\": [\"16672694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"COS-7, HEK293, HeLa cells; Xenopus oocytes; single-channel patch clamp; pharmacological activation of PKA/PKC; site-directed mutagenesis\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-channel electrophysiology with mutagenesis across multiple cell lines and native neurons\",\n      \"pmids\": [\"17540699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot; site-directed mutagenesis of translation initiation sites; single-channel patch clamp in mammalian cells\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with biochemical and electrophysiological validation across multiple constructs\",\n      \"pmids\": [\"18845607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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).\",\n      \"method\": \"Whole-cell patch clamp in entorhinal cortex slices; pharmacological dissection with specific receptor/kinase inhibitors; Morris water maze behavioral assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology in native neurons with pharmacological pathway dissection, behavioral outcome linked to TREK-2 activation\",\n      \"pmids\": [\"19640481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch clamp in entorhinal cortex slices; pharmacological inhibitors; site-directed mutagenesis of TREK-2 PKA site\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus electrophysiology in native neurons, pathway fully dissected pharmacologically\",\n      \"pmids\": [\"19244246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR; immunoblot; single-channel and whole-cell patch clamp; siRNA knockdown; pharmacological PI kinase inhibition\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown confirming molecular identity, pharmacological pathway dissection, multiple electrophysiological configurations\",\n      \"pmids\": [\"19439530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell (perforated and ruptured) and single-channel patch clamp in CHO cells; pharmacological inhibitors; inside-out patches\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological dissection in single lab, single cell type, no mutagenesis confirmation\",\n      \"pmids\": [\"17410710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry; siRNA knockdown; whole-cell patch clamp; in vivo behavioral assay (spontaneous foot lifting)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with defined electrophysiological and behavioral phenotypes, corroborated by in vivo expression-function correlation\",\n      \"pmids\": [\"24453337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"TREK-2 knockout mice; behavioral thermosensory and nociceptive assays; peripheral C-fiber electrophysiology\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined behavioral and electrophysiological phenotypes\",\n      \"pmids\": [\"25239074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Two-electrode voltage clamp in Xenopus oocytes; whole-cell patch clamp in DRG neurons; site-directed mutagenesis\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with electrophysiology confirming structural basis of pharmacological selectivity, validated in native DRG neurons\",\n      \"pmids\": [\"25409575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — tandem construct plus reciprocal co-IP plus electrophysiology, validated in native tissue\",\n      \"pmids\": [\"27129242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types, multiple patch configurations, co-expression of voltage-sensitive phosphatase, confirmed endogenous regulation\",\n      \"pmids\": [\"27283411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"195 μs all-atom unbiased molecular dynamics simulations; Markov state modeling; free-energy barrier calculations based on published TREK-2 crystal structures\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (computational) / Weak — extensive MD simulation with Markov modeling, but no direct experimental validation of the pinched state in the abstract\",\n      \"pmids\": [\"28377596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Inside-out patch clamp in HEK293T cells expressing WT and mutant human TREK-2; intracellular pH manipulation; intracellular ATP application\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with electrophysiology defining specific residues for two regulatory mechanisms\",\n      \"pmids\": [\"28988317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology with reversal potential measurements under stretch; based on structural data from prior crystal structures\",\n      \"journal\": \"Channels (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — electrophysiological selectivity measurements in single lab, single method\",\n      \"pmids\": [\"28723241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown in 3T3-L1 cells; western blot for C/EBPβ, C/EBPδ, Akt phosphorylation; cell proliferation assays during adipocyte differentiation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA knockdown with defined molecular phenotype in single lab, single cell type\",\n      \"pmids\": [\"25501330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Thallium flux cell-based assay for screening; whole-cell patch clamp electrophysiology; site-directed mutagenesis of TREK2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological characterization with mutagenesis, but binding site not positively identified; single lab\",\n      \"pmids\": [\"31564414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Covalently linked tandem TRESK/TREK-2 construct; single-channel patch clamp; pharmacological characterization; native DRG/trigeminal ganglion neuron recordings\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — tandem construct enforcing subunit stoichiometry plus pharmacological fingerprinting plus native cell validation\",\n      \"pmids\": [\"32641496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; cell surface biotinylation assay; site-directed mutagenesis of TREK-2 C-terminus; heterologous expression\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP with mutagenesis confirming binding site, single lab, no in vivo confirmation\",\n      \"pmids\": [\"37296621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell and single-channel patch clamp in B35 cells and HEK293 transfected cells; N-terminal deletion mutant; RT-PCR; western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mutagenesis with electrophysiology, but single lab and limited mechanistic detail in abstract\",\n      \"pmids\": [\"34502229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry; immunocytochemistry; western blotting; in vivo pharmacological manipulation (GDNF subcutaneous infusion); behavioral allodynia assays\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo and in vitro pharmacological manipulation with functional outcomes, single lab\",\n      \"pmids\": [\"35907583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Camelid nanobody generation; X-ray crystallography; cryo-EM; electrophysiological channel activity assays; structure-guided nanobody engineering\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution structures (X-ray and cryo-EM) with functional validation and structure-guided design, multiple orthogonal methods\",\n      \"pmids\": [\"38755204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Native mass spectrometry; functional activity correlation assays\",\n      \"journal\": \"Journal of the American Society for Mass Spectrometry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — native MS with functional correlation, single lab, no mutagenesis\",\n      \"pmids\": [\"38843438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint; multiple constructs and pharmacological tools but not yet peer-reviewed; single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological and genetic dissection in oocytes, TREK-2 activation by ionomycin confirmed but mechanistic detail (mutagenesis) primarily shown for TREK-1; single lab\",\n      \"pmids\": [\"41457157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Inside-out patch clamp in COS-7 cells; TREK2/TASK3 chimeric constructs; application of oxidizing (DTNB) and reducing (DTT) agents\",\n      \"journal\": \"The Korean journal of physiology & pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — chimera mutagenesis with electrophysiology, single lab, narrow focus\",\n      \"pmids\": [\"19967058\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TREK-2 (KCNK10/K2P10.1) is a polymodal two-pore domain background K+ channel that is activated by membrane stretch, polyunsaturated fatty acids, intracellular acidification (via E332 in the proximal C-terminus), heat (via a C-terminal temperature-responsive element requiring the microtubule/MAP2 network), volatile anesthetics, calcineurin (calcium-dependent, anchored by AKAP5), and disinhibition of PKA-mediated tonic suppression (downstream of Gi-coupled receptors); it is tonically inhibited by PIP2 maintained through intracellular ATP/PI kinase, and acutely inhibited by PKC-mediated phosphorylation at S326/S359 (downstream of Gq-coupled receptors) and by β-COP-mediated reduction of surface expression; alternative translation initiation from three N-terminal methionines produces isoforms whose N-terminus length controls single-channel conductance (small ~52 pS vs large ~220 pS), while the selectivity filter remains stable and K+-selective during stretch activation; TREK-2 can form functional heterodimers with TREK-1 or TRESK, expanding the diversity of background K+ conductances in native neurons including DRG nociceptors where it hyperpolarizes IB4+ C-fibers and limits spontaneous pain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. It is activated by membrane stretch, polyunsaturated fatty acids, lysophospholipids, intracellular acidification, and volatile anesthetics, and is outwardly rectifying [#0, #1]; the proximal C-terminal residues E332/K330 are required for activation by acidic intracellular pH [#17], and stretch shifts the channel from a 'down' to an 'up' state without altering its strict K+ selectivity [#16, #18]. 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 [#3, #27]. 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 [#9, #15]. 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 [#2, #4, #5]; conversely, disinhibition of tonic PKA suppression downstream of Gi-coupled GABA(B) and α2A-adrenergic receptors activates the channel and depresses neuronal excitability [#7, #8]. Single-channel conductance is determined by N-terminus length through alternative translation initiation, yielding small (~52 pS) and large (~185–224 pS) phenotypes [#6]. TREK-2 forms functional heterodimers with TREK-1 and with TRESK, generating channels of intermediate biophysical and pharmacological properties in native sensory neurons [#14, #21]. 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 [#11, #12]. High-resolution nanobody-bound structures have defined extracellular and Cap-domain sites for channel modulation [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Heterologous expression with whole-cell and single-channel patch clamp\",\n      \"pmids\": [\"10880510\", \"10747911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of stimulus sensing not resolved\", \"Native cellular role not yet established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved how cAMP suppresses the channel by mapping PKA-dependent inhibition to a defined C-terminal serine and identifying tissue-specific splice isoforms.\",\n      \"evidence\": \"cDNA cloning, HEK293 expression, site-directed mutagenesis (S364A), whole-cell patch clamp\",\n      \"pmids\": [\"11897838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream receptors driving cAMP regulation not yet identified\", \"Isoform-specific physiology unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Separated heat gating from chemical gating, showing thermosensitivity is mechanistically distinct from the C-terminus-dependent fatty-acid/proton response.\",\n      \"evidence\": \"Temperature ramps and TREK-2/TASK-3 C-terminal chimeras in COS-7 cells and native neurons\",\n      \"pmids\": [\"15677687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular element conferring heat sensitivity not localized in this study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the mechanism of Gq-receptor inhibition, showing PKC phosphorylation at S326/S359 rather than PIP2 depletion, Ca2+, or DAG mediates acute muscarinic inhibition.\",\n      \"evidence\": \"M3 receptor co-expression, site-directed mutagenesis, pharmacological controls, patch clamp\",\n      \"pmids\": [\"16672694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay with PIP2 regulation under sustained signaling not fully resolved here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected phosphorylation to single-channel behavior, showing PKA/PKC phosphorylation shifts gating modes and conductance, and added an MLCK-dependent oxidative activation route.\",\n      \"evidence\": \"Single-channel patch clamp with kinase activators and phosphomimetic mutants; H2O2/MLCK pharmacology in CHO cells\",\n      \"pmids\": [\"17540699\", \"17410710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"H2O2/MLCK intermediate not identified at molecular level\", \"Physiological context of oxidative activation unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mutagenesis of translation start sites, Western blot, single-channel patch clamp; DTNB chimera mapping (aa 353-383)\",\n      \"pmids\": [\"18845607\", \"19967058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of conductance switching in vivo unknown\", \"Identity of oxidation-sensitive residues not pinpointed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Native entorhinal cortex slice patch clamp with pathway dissection and PKA-site mutagenesis; siRNA and PI-kinase pharmacology in B cells\",\n      \"pmids\": [\"19640481\", \"19244246\", \"19439530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Behavioral significance of cortical TREK-2 modulation incompletely defined\", \"Quantitative coupling of PIP2 to gating not yet resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the in vivo nociceptive and thermosensory role, showing TREK-2 sets C-fiber resting potential, limits spontaneous pain, and shapes thermal/mechanical perception.\",\n      \"evidence\": \"siRNA knockdown and knockout mice with electrophysiology and behavioral pain/thermosensory assays; plus a metabolic role in adipogenesis\",\n      \"pmids\": [\"24453337\", \"25239074\", \"25501330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Tandem constructs, co-immunoprecipitation, single-channel patch clamp; voltage-sensitive phosphatase and ATP/PI-kinase manipulation across multiple cell types\",\n      \"pmids\": [\"27129242\", \"27283411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and abundance of native heterodimers unquantified\", \"Switch point between PIP2 activation and inhibition not mechanistically defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Inside-out patch clamp with mutagenesis; 195-µs all-atom MD with Markov modeling; reversal-potential selectivity measurements under stretch\",\n      \"pmids\": [\"28988317\", \"28377596\", \"28723241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pinched-filter state lacks direct experimental confirmation (computational)\", \"How a single residue couples two distinct regulatory inputs unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended heteromeric diversity to TRESK, showing TRESK/TREK-2 heterodimers in sensory neurons combine calcineurin-dependent regulation with TREK-2-selective pharmacology.\",\n      \"evidence\": \"Covalently linked tandem construct, single-channel patch clamp, pharmacological fingerprinting, native DRG/trigeminal recordings\",\n      \"pmids\": [\"32641496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological prevalence of TRESK/TREK-2 heterodimers unquantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Camelid nanobody generation, crystallography, cryo-EM, structure-guided engineering; native mass spectrometry of lipid binding\",\n      \"pmids\": [\"38755204\", \"38843438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic applicability of nanobody modulators untested in vivo\", \"Lipid-affinity to gating link (Medium-confidence) lacks mutagenesis\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"41457157\", \"37296621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Calcineurin mutagenesis primarily validated for TREK-1, not TREK-2\", \"Thermosensitivity element findings remain a preprint\", \"β-COP trafficking effect not confirmed in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"Not addressed by the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 1, 3, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [15, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 8, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 8, 15]}\n    ],\n    \"complexes\": [\n      \"TREK-1/TREK-2 heterodimer\",\n      \"TRESK/TREK-2 heterodimer\"\n    ],\n    \"partners\": [\n      \"KCNK2\",\n      \"KCNK18\",\n      \"AKAP5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}