KCNK2

Summary

KCNK2 (potassium two pore domain channel subfamily K member 2, HGNC:6277) is a protein-coding gene on chromosome 1q41, encoding Potassium channel subfamily K member 2 (O95069). K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.

This gene encodes one of the members of the two-pore-domain background potassium channel protein family. This type of potassium channel is formed by two homodimers that create a channel that leaks potassium out of the cell to control resting membrane potential. The channel can be opened, however, by certain anesthetics, membrane stretching, intracellular acidosis, and heat. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3776 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 40 total — 1 pathogenic
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001017425

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6277
Approved symbol	KCNK2
Name	potassium two pore domain channel subfamily K member 2
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	K2p2.1, TREK-1
Ensembl gene	ENSG00000082482
Ensembl biotype	protein_coding
OMIM	603219
Entrez	3776

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 4 nonsense_mediated_decay

ENST00000391894, ENST00000391895, ENST00000444842, ENST00000457122, ENST00000467031, ENST00000470177, ENST00000474771, ENST00000478774, ENST00000486921, ENST00000964758

RefSeq mRNA: 3 — MANE Select: NM_001017425 NM_001017424, NM_001017425, NM_014217

CCDS: CCDS31024, CCDS41466, CCDS41467

Canonical transcript exons

ENST00000444842 — 7 exons

Exon	Start	End
ENSE00001154082	215124633	215124750
ENSE00001846192	215082737	215083431
ENSE00002264899	215234828	215237090
ENSE00003513413	215194953	215195092
ENSE00003517429	215086368	215086678
ENSE00003648847	215169199	215169359
ENSE00003662466	215171997	215172183

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 94.96.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4753 / max 415.2769, expressed in 681 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8568	1.1036	424
8560	0.6558	179
8559	0.5968	174
8563	0.5205	177
8571	0.4917	184
8573	0.4192	184
8562	0.3761	144
8569	0.3400	196
8564	0.2836	121
8561	0.2803	120

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	94.96	gold quality
right adrenal gland cortex	UBERON:0035827	92.87	gold quality
left adrenal gland	UBERON:0001234	92.55	gold quality
left adrenal gland cortex	UBERON:0035825	92.43	gold quality
right adrenal gland	UBERON:0001233	92.35	gold quality
cortical plate	UBERON:0005343	90.33	gold quality
adrenal cortex	UBERON:0001235	89.24	gold quality
adrenal gland	UBERON:0002369	89.19	gold quality
calcaneal tendon	UBERON:0003701	88.29	gold quality
adrenal tissue	UBERON:0018303	84.55	gold quality
ganglionic eminence	UBERON:0004023	82.49	gold quality
cartilage tissue	UBERON:0002418	82.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.74	gold quality
tendon	UBERON:0000043	77.55	gold quality
tibial nerve	UBERON:0001323	76.72	gold quality
prefrontal cortex	UBERON:0000451	73.66	gold quality
caudate nucleus	UBERON:0001873	73.24	gold quality
ventricular zone	UBERON:0003053	72.50	gold quality
putamen	UBERON:0001874	71.82	gold quality
amygdala	UBERON:0001876	69.89	gold quality
nucleus accumbens	UBERON:0001882	69.36	gold quality
embryo	UBERON:0000922	69.35	gold quality
cingulate cortex	UBERON:0003027	69.12	gold quality
left lobe of thyroid gland	UBERON:0001120	68.95	gold quality
anterior cingulate cortex	UBERON:0009835	68.83	gold quality
skin of abdomen	UBERON:0001416	68.49	gold quality
right lobe of thyroid gland	UBERON:0001119	68.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	68.33	gold quality
thyroid gland	UBERON:0002046	68.07	gold quality
body of stomach	UBERON:0001161	67.40	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting KCNK2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-6772-5P	99.94	67.01	577

Literature-anchored findings (GeneRIF, showing 40)

• TREK-1 channels may function as sensors that couple the metabolic state of the cell to membrane potential, perhaps through an associated ATP-binding protein (PMID:12368289)
• During hypoxia, modulation of hTREK1 cannot be accomplished by parameters known to be perturbed in brain ischemia. hTREK1 regulation in brain will be more relevant during alkalosis than during ischemia or acidosis. (PMID:14522822)
• TREK-1 is inhibited by fluoxetine and norfluoxetine. (PMID:15685212)
• hypoxic inhibition: (a) requires the C-terminal domain of the channel; (b) does not involve redox modulation of the C-terminal domain cysteine residues C365 and C399; and (c) is critically dependent on the glutamate residue at position 306 (PMID:15883010)
• receptor- and kinase-induced inhibition of TREK-1 background potassium channels is mediated by sequential phosphorylation (PMID:16006563)
• human osteoblasts functionally express TREK-1 and that these channels contribute, at least in part, to the resting membrane potential of human osteoblast cells. We hypothesise a possible role for TREK-1 in mechanotransduction, leading to bone remodelling. (PMID:16250016)
• VOCCs and TREK channels have been implicated in mechanotransduction signaling pathways in numerous connective tissue cell types. (PMID:17035301)
• TREK1, the most thoroughly studied K(2P) channel, has a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain and depression–{REVIEW} (PMID:17375039)
• These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response. (PMID:18288090)
• voltage-dependent C-type gating acceleration by protons represents a novel mechanism for K2P2.1 outward rectification. (PMID:18474599)
• (Review) KCNK2, the gene encoding K2P2.1, can generate either full-length or K2P2.1D1-56 via alternative translation initiation, a mechanism which increases protein diversity by giving rise to two or more proteins from a single mRNA strand. (PMID:18579071)
• Both TASK-3 and TREK-1 are functionally operational in the adrenocortical H295R cell line, modulate membrane potential and aldosterone secretion. (PMID:18854423)
• Results highlight the important role of K(2P)2.1 channels as receptors for mediators known to cause nociception. (PMID:19130888)
• These findings indicate that TREK1 genotypes are associated with individual differences in reward-related brain activity. (PMID:19621370)
• KCNK2 is related to the susceptibility to major depressive disorder (PMID:19741570)
• Results describe the regulation of neuronal K(2P)2.1 (KCNK2, TREK-1) channel activity by resting membrane potential. (PMID:19837167)
• these data suggest that beta-COP plays a critical role in the forward transport of TREK1 channel to the plasma membrane. (PMID:20362547)
• role for TREK-1 in contributing to uterine quiescence during gestation (PMID:20811500)
• The data of this study suggested that TREK-1 is associated with NSC proliferation and probably is a modulator of the effect that fluoxetine attenuates the inhibitory neurogenesis induced by glucocorticoid hormones. (PMID:21069514)
• inhibition of TREK1 current by fluoxetine is found to be accompanied by dissociation of the C-terminal domain from the membrane. (PMID:21262820)
• These results demonstrate that the primary activation mechanisms in TREK-1 reside close to, or within the selectivity filter and do not involve gating at the cytoplasmic bundle crossing. (PMID:21822218)
• Cochlin interacts with TREK-1 and annexin A2. (PMID:21886777)
• Potassium channels, in particular K2P channels, are expressed and functional in the apical membrane of airway epithelial cells (PMID:21964404)
• the important role of selectivity filter gating in the regulation of TREK-1 by the extracellular K(+) and proton. (PMID:21965685)
• TREK-1 is expressed by both nucleus pulposus and annulus fibrosus cells of the human intervertebral disc. (PMID:22563662)
• each of four TREK-1 splice variants interacts with full-length wild-type TREK-1 and in vivo, such interactions may contribute to a preterm labor phenotype. (PMID:22811574)
• we report the expression of Trek-1 in human alveolar epithelial cells and propose that Trek-1 deficiency may alter both IL-6 translation and transcription in AECs without affecting Ca(2+) signaling (PMID:23275623)
• TASK and TREK-1 are involved in regulation of cell proliferation and in control of resting membrane potentials in endometrial epithelial cells. (PMID:23305490)
• High TREK-1 expression is associated with epithelial ovarian cancer. (PMID:23479219)
• In human embryonic kidney (HEK-293) cells stably expressing TREK-1, outward currents at 80 mV increased from 91.0 +/- 23.8 to 247.5 +/- 73.3 pA/pF. (PMID:23804201)
• study analyzed the role of TWIK-related potassium channel-1 (TREK1)in endothelial cells and the blood-brain barrier(BBB); blocking TREK1 increased leukocyte transmigration; TREK1 activation had the opposite effect (PMID:23933981)
• Activation of K(2)P channel-TREK1 mediates the neuroprotection induced by sevoflurane preconditioning. (PMID:24154701)
• results suggest that the TREK-1e splice variant may interfere with the vesicular traffic of full-length TREK-1 channels from the ER to the plasma membrane. (PMID:24196565)
• A number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. (PMID:24509840)
• TREK-1 deficient alveolar epithelial cells have less F-actin and are more deformable making them more resistant to stretch-induced injury. (PMID:24586773)
• Response of the human detrusor to stretch is regulated by TREK-1 (PMID:24801307)
• Modulation of K2P 2.1 and K2P 10.1 K(+) channel sensitivity to carvedilol by alternative mRNA translation initiation (PMID:25168769)
• PLD2, but not PLD1, directly binds to the C terminus of TREK1 and TREK2. (PMID:25197053)
• During conductance simulation experiments, both TASK-3 and TREK-1 channels were able to repolarise the membrane once AP threshold was reached (PMID:25482670)
• Nasal epithelia express Trek1 that can be suppressed by allergic response. (PMID:25529528)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnk2b	ENSDARG00000007151
danio_rerio	kcnk2a	ENSDARG00000055123
mus_musculus	Kcnk2	ENSMUSG00000037624
rattus_norvegicus	Kcnk2	ENSRNOG00000002653
drosophila_melanogaster	Ork1	FBGN0017561
drosophila_melanogaster	Task7	FBGN0037690
drosophila_melanogaster	Task6	FBGN0038165
drosophila_melanogaster	CG10864	FBGN0038621
drosophila_melanogaster	CG42340	FBGN0259242
caenorhabditis_elegans		WBGENE00006661
caenorhabditis_elegans		WBGENE00006674
caenorhabditis_elegans		WBGENE00006675
caenorhabditis_elegans		WBGENE00006679
caenorhabditis_elegans		WBGENE00006685
caenorhabditis_elegans		WBGENE00006686
caenorhabditis_elegans		WBGENE00006695
caenorhabditis_elegans		WBGENE00006696

Paralogs (14): KCNK16 (ENSG00000095981), KCNK6 (ENSG00000099337), KCNK10 (ENSG00000100433), KCNK15 (ENSG00000124249), KCNK17 (ENSG00000124780), KCNK1 (ENSG00000135750), KCNK13 (ENSG00000152315), KCNK5 (ENSG00000164626), KCNK9 (ENSG00000169427), KCNK3 (ENSG00000171303), KCNK7 (ENSG00000173338), KCNK4 (ENSG00000182450), KCNK12 (ENSG00000184261), KCNK18 (ENSG00000186795)

Protein

Protein identifiers

Potassium channel subfamily K member 2 — O95069 (reviewed: O95069)

Alternative names: Outward rectifying potassium channel protein TREK-1, TREK-1 K(+) channel subunit, Two pore domain potassium channel TREK1, Two pore potassium channel TPKC1

All UniProt accessions (8): O95069, B4DGU6, C9JDK1, C9JXY2, F8WDE6, Q6ZW95, U3N6F0, U3N834

UniProt curated annotations — full annotation on UniProt →

Function. K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an ‘ion flux gating’ mode where outward but not inward ion flow opens the gate. Converts to voltage-independent ’leak’ conductance mode upon stimulation by various stimuli including mechanical membrane stretch, acidic pH, heat and lipids. Reversibly converts between a voltage-insensitive K(+) ’leak’ channel and a voltage-dependent outward rectifying K(+) channel in a phosphorylation-dependent manner. Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties. In trigeminal ganglia sensory neurons, the heterodimer of KCNK2/TREK-1 and KCNK18/TRESK inhibits neuronal firing and neurogenic inflammation by stabilizing the resting membrane potential at K(+) equilibrium potential as well as by regulating the threshold of action potentials and the spike frequency. At trigeminal A-beta afferent nerves, the heterodimer of KCNK2/TREK-1 and KCNK4/TRAAK is mostly coexpressed at nodes of Ranvier where it conducts voltage-independent mechanosensitive and thermosensitive currents, allowing rapid action potential repolarization, high speed and high frequence saltatory conduction on myelinated nerves to ensure prompt sensory responses. In hippocampal astrocytes, the heterodimer of KCNK2/TREK-1 and KCNK1/TWIK-1 allows passive K(+) conductance under basal conditions, but changes ion selectivity and becomes permeable to L-glutamate and Cl(-) ions upon binding to G-protein subunit GNG4 in stimulated astrocytes. Mediates rapid L-glutamate release in response to activation of G-protein-coupled receptors, such as F2R and CNR1. In hippocampal pyramidal neurons, the homodimer of KCNK2/TREK-1 contributes to gamma-aminobutyric acid (GABA) B-induced slow inhibitory postsynaptic potential. Associates with AKAP5 and Gs-protein-coupled receptor B2AR at postsynaptic dense bodies and converts to a leak channel no longer sensitive to stimulation by arachidonic acid, acidic pH or mechanical stress, nor inhibited by Gq-coupled receptors but still under the negative control of Gs-coupled receptors. Permeable to other monovalent cations such as Rb(+) and Cs(+). Does not display channel activity but reduces the channel activity of isoform 1 and isoform 2 and reduces cell surface expression of isoform 2.

Subunit / interactions. Homodimer; disulfide-linked (Ref.15). Forms heterodimers with other 2-pore domain K(+) channel subunits, such as KCNK1, KCNK4, KCNK10 and KCNK18. Interacts with AKAP5; the channel is recruited to postsynaptic microdomains by AKAP5 where it can integrate neurotransmitter receptor signals. Part of a complex composed of AKAP5 and ADRB2. Upon AKAP5 binding, the channel is no longer sensitive to intracellular acidification, membrane stretch or arachidonic acid stimuli. Interacts with POPDC1; the interaction enhances KCNK2 surface expression and is inhibited by cAMP. Interacts (via N-terminus) with G-protein subunit GNG4 (via C-terminus); this interaction confers ion selectivity to L-glutamate and Cl(-) anions.

Subcellular location. Cell membrane Cell membrane Endoplasmic reticulum membrane Cell projection. Axon. Cell projection. Dendrite. Postsynaptic density membrane. Cell membrane. Sarcolemma.

Tissue specificity. Detected in kidney, adrenal gland and brain where it is preferentially expressed in the amygdala but not found in thalamus, hypothalamus, hippocampus or substantia nigra.

Post-translational modifications. Phosphorylation at Ser-348 controls the reversible conversion from a leak channel to a voltage-dependent channel.

Activity regulation. Activated by various stimuli including intracellular acidic pH, mechanical stretch and polyunsaturated fatty acids such as arachidonic acid. Activated by volatile anesthetics such as chloroform, halothane, and isoflurane.

Domain organisation. Each subunit contributes two pore-forming domains 1 and 2 which assemble to form a single pore with M2 and M4 transmembrane helices lining the central cavity and M1 and M3 facing the lipid bilayer. The transmembrane helices are bridged by the selectivity filters 1 and 2 carrying a signature sequence TxTTxGYGD that coordinate the permeant ions. Up to four ions can simultaneously occupy the selectivity filter and at least two elementary charges must translocate across the filter to convert it into the open conformation. The C-terminal region of isoform 4 mediates its intracellular retention.

Similarity. Belongs to the two pore domain potassium channel (TC 1.A.1.8) family.

Isoforms (4)

UniProt ID	Names	Canonical?
O95069-1	1, TREK-1b	yes
O95069-2	2, TREK-1a
O95069-3	3, TREK-1c
O95069-4	4, TREK-1e

RefSeq proteins (3): NP_001017424, NP_001017425, NP_055032 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003280	2pore_dom_K_chnl	Family
IPR003976	2pore_dom_K_chnl_TREK	Family
IPR013099	K_chnl_dom	Domain

Pfam: PF07885

Catalyzed reactions (Rhea), 5 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• chloride(in) = chloride(out) (RHEA:29823)
• L-glutamate(out) = L-glutamate(in) (RHEA:66336)
• Rb(+)(in) = Rb(+)(out) (RHEA:78547)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (54 total): binding site 14, helix 8, region of interest 6, transmembrane region 4, splice variant 4, topological domain 3, sequence conflict 3, intramembrane region 2, glycosylation site 2, mutagenesis site 2, chain 1, site 1, modified residue 1, disulfide bond 1, turn 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4TWK	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95069-F1	76.39	0.37

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 141 (ph sensor)

Ligand- & substrate-binding residues (14): 157; 157; 158; 158; 159; 159; 160; 266; 266; 267; 267; 268 …

Post-translational modifications (1): 348

Disulfide bonds (1): 108

Glycosylation sites (2): 110, 134

Mutagenesis-validated functional residues (2):

Position	Phenotype
348	mimics non-phosphorylated state and has no effect on leak channel activity.
348	phosphomimetic mutant which causes switch to voltage-dependent outward rectifier channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1299503	TWIK related potassium channel (TREK)
R-HSA-5576886	Phase 4 - resting membrane potential
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-1296346	Tandem pore domain potassium channels
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 303 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MEMORY, GOBP_GLUTAMATE_SECRETION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, REACTOME_TANDEM_PORE_DOMAIN_POTASSIUM_CHANNELS, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, REACTOME_POTASSIUM_CHANNELS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION

GO Biological Process (22): cardiac ventricle development (GO:0003231), G protein-coupled receptor signaling pathway (GO:0007186), memory (GO:0007613), glutamate secretion (GO:0014047), neuronal action potential (GO:0019228), regulation of synaptic transmission, GABAergic (GO:0032228), response to axon injury (GO:0048678), detection of mechanical stimulus involved in sensory perception of touch (GO:0050976), negative regulation of cardiac muscle cell proliferation (GO:0060044), cellular response to hypoxia (GO:0071456), potassium ion transmembrane transport (GO:0071805), cochlea development (GO:0090102), chemical synaptic transmission, postsynaptic (GO:0099565), positive regulation of cellular response to hypoxia (GO:1900039), chloride transmembrane transport (GO:1902476), cellular response to arachidonate (GO:1904551), negative regulation of DNA biosynthetic process (GO:2000279), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), response to mechanical stimulus (GO:0009612), monoatomic ion transmembrane transport (GO:0034220), regulation of membrane potential (GO:0042391)

GO Molecular Function (10): outward rectifier potassium channel activity (GO:0015271), potassium channel inhibitor activity (GO:0019870), ligand-gated channel activity (GO:0022834), potassium ion leak channel activity (GO:0022841), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), mechanosensitive potassium channel activity (GO:0098782), voltage-gated potassium channel activity (GO:0005249), potassium channel activity (GO:0005267)

GO Cellular Component (20): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), cell surface (GO:0009986), apical plasma membrane (GO:0016324), dendrite (GO:0030425), node of Ranvier (GO:0033268), sarcolemma (GO:0042383), neuronal cell body (GO:0043025), calyx of Held (GO:0044305), astrocyte projection (GO:0097449), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic density membrane (GO:0098839), membrane (GO:0016020), axon (GO:0030424), cell projection (GO:0042995), axon terminus (GO:0043679), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Tandem pore domain potassium channels	1
Cardiac conduction	1
Neuronal System	1
Potassium Channels	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
potassium channel activity	4
cellular anatomical structure	4
postsynapse	2
neuron projection	2
cardiac chamber development	1
G protein-coupled receptor activity	1
signal transduction	1
learning or memory	1
dicarboxylic acid transport	1
acidic amino acid transport	1
secretion by cell	1
nitrogen compound transport	1
action potential	1
transmission of nerve impulse	1
modulation of chemical synaptic transmission	1
synaptic transmission, GABAergic	1
response to wounding	1
detection of mechanical stimulus involved in sensory perception	1
sensory perception of touch	1
negative regulation of cell population proliferation	1
negative regulation of cardiac muscle tissue growth	1
cardiac muscle cell proliferation	1
regulation of cardiac muscle cell proliferation	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
inner ear development	1
anatomical structure development	1
cell surface receptor signaling pathway	1
chemical synaptic transmission	1
nervous system process	1
positive regulation of cellular process	1
positive regulation of response to stimulus	1
cellular response to hypoxia	1
regulation of cellular response to hypoxia	1
chloride transport	1
monoatomic anion transmembrane transport	1
cellular response to fatty acid	1

Protein interactions and networks

STRING

764 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNK2	KCNK1	O00180	953
KCNK2	KRT76	Q01546	903
KCNK2	POPDC2	Q9HBU9	765
KCNK2	POPDC1	Q8NE79	752
KCNK2	SPTBN4	Q9H254	723
KCNK2	PIEZO1	Q92508	710
KCNK2	KCNK4	Q9NYG8	700
KCNK2	KCNK10	P57789	695
KCNK2	PIEZO2	Q9H5I5	647
KCNK2	COCH	O43405	639
KCNK2	TRPV1	Q8NER1	634
KCNK2	TRPM8	Q7Z2W7	631
KCNK2	TRPA1	O75762	626
KCNK2	PLD2	O14939	622
KCNK2	PRKACA	P17612	622
KCNK2	PRKACB	P22694	622
KCNK2	PRKACG	P22612	622

IntAct

0 interactions, top by confidence:

BioGRID (1): KCNK2 (Negative Genetic)

ESM2 similar proteins: A0A1D8PTL7, A2WNZ9, A2YGP9, A5LFX5, A8MYU2, D4A6Z8, F4HWB6, O14197, O16242, O54982, O60146, O95069, P28584, P38329, P40310, P47144, P47564, P47946, P75323, P87122, P92960, P97438, Q0D9S3, Q0JNB6, Q10065, Q10937, Q38849, Q38898, Q54DA4, Q653P0, Q6H501, Q6SZ87, Q759P7, Q7XPF7, Q7XPF8, Q7XUW4, Q84TI7, Q8L481, Q8L4K5, Q920B6

Diamond homologs: G3V8R8, G3V8V5, G5E845, O00180, O08581, O14649, O17185, O35111, O54912, O88454, O95069, O95279, P57789, P97438, Q0P5A0, Q23435, Q3LS21, Q3TBV4, Q5RD07, Q5UE96, Q5VSE6, Q63ZI0, Q6Q1P3, Q6VV64, Q7Z418, Q8BUW1, Q8R454, Q8R5I0, Q920B6, Q96T54, Q96T55, Q9ERS1, Q9ES08, Q9H427, Q9HB14, Q9HB15, Q9JIS4, Q9JL58, Q9NPC2, Q9NYG8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

40 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	27
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3248093	NC_000001.10:g.(?190829412)(216061974_?)del	Pathogenic

SpliceAI

1269 predictions. Top by Δscore:

Variant	Effect	Δscore
1:215169194:TAAA:T	acceptor_loss	1.0000
1:215169195:AAAG:A	acceptor_gain	1.0000
1:215169197:A:G	acceptor_gain	1.0000
1:215169197:AGGAT:A	acceptor_loss	1.0000
1:215169198:G:GG	acceptor_gain	1.0000
1:215169349:A:G	donor_gain	1.0000
1:215169355:TTATT:T	donor_gain	1.0000
1:215169356:TATT:T	donor_gain	1.0000
1:215169357:ATT:A	donor_gain	1.0000
1:215169358:TT:T	donor_gain	1.0000
1:215169358:TTGTG:T	donor_loss	1.0000
1:215169359:TG:T	donor_loss	1.0000
1:215169360:G:GG	donor_gain	1.0000
1:215169360:GT:G	donor_loss	1.0000
1:215169362:GA:G	donor_gain	1.0000
1:215169362:GAGTA:G	donor_loss	1.0000
1:215169363:A:AG	donor_gain	1.0000
1:215169364:G:GG	donor_gain	1.0000
1:215171996:GAA:G	acceptor_gain	1.0000
1:215194944:T:A	acceptor_gain	1.0000
1:215194948:TCCA:T	acceptor_loss	1.0000
1:215194949:CCAG:C	acceptor_loss	1.0000
1:215194950:CA:C	acceptor_loss	1.0000
1:215194951:A:AG	acceptor_gain	1.0000
1:215194951:AGGT:A	acceptor_gain	1.0000
1:215194951:AGGTG:A	acceptor_gain	1.0000
1:215194952:G:GA	acceptor_gain	1.0000
1:215194952:GGT:G	acceptor_gain	1.0000
1:215194952:GGTG:G	acceptor_gain	1.0000
1:215194952:GGTGG:G	acceptor_gain	1.0000

AlphaMissense

2766 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:215086539:T:C	L73P	1.000
1:215086547:G:A	G76R	1.000
1:215086547:G:C	G76R	1.000
1:215086548:G:A	G76E	1.000
1:215124699:T:A	W142R	1.000
1:215124699:T:C	W142R	1.000
1:215124701:G:C	W142C	1.000
1:215124701:G:T	W142C	1.000
1:215124730:G:A	G152D	1.000
1:215169199:G:A	G159E	1.000
1:215169205:G:A	G161E	1.000
1:215169264:G:A	G181R	1.000
1:215169264:G:C	G181R	1.000
1:215169265:G:A	G181E	1.000
1:215169265:G:T	G181V	1.000
1:215169271:C:A	P183H	1.000
1:215169280:G:A	G186D	1.000
1:215169286:T:C	L188P	1.000
1:215172151:T:C	L264P	1.000
1:215172162:G:A	G268R	1.000
1:215172162:G:C	G268R	1.000
1:215172163:G:A	G268E	1.000
1:215172168:G:T	G270C	1.000
1:215172169:G:A	G270D	1.000
1:215172169:G:T	G270V	1.000
1:215195003:T:A	W292R	1.000
1:215195003:T:C	W292R	1.000
1:215195015:G:A	G296R	1.000
1:215195015:G:C	G296R	1.000
1:215195019:T:C	L297P	1.000

dbSNP variants (sampled 300 via entrez): RS1000017335 (1:215179717 C>T), RS1000028722 (1:215208910 C>T), RS1000029766 (1:215044936 C>T), RS1000034130 (1:215134672 G>A), RS1000046033 (1:215199392 C>T), RS1000069705 (1:215179928 G>T), RS1000070644 (1:215133805 C>T), RS1000092972 (1:215213093 G>T), RS1000109593 (1:215075281 T>A,C), RS1000118441 (1:215163423 C>A,T), RS1000120834 (1:215225867 C>G), RS1000141863 (1:215135334 A>G), RS1000174756 (1:215096872 AG>A), RS1000175710 (1:215063561 A>G), RS1000225877 (1:215138992 C>T)

Disease associations

OMIM: gene MIM:603219 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST006483_39	Lung function (FVC)	4.000000e-09
GCST010697_3	Cortical surface area (min-P)	1.000000e-11
GCST010698_69	Subcortical volume (min-P)	9.000000e-15
GCST010699_66	Brain morphology (min-P)	3.000000e-22
GCST010700_30	Cortical thickness (MOSTest)	9.000000e-09
GCST010701_117	Cortical surface area (MOSTest)	3.000000e-11
GCST010702_166	Subcortical volume (MOSTest)	3.000000e-18
GCST010703_108	Brain morphology (MOSTest)	5.000000e-20
GCST011618_7	Cortical thickness	3.000000e-19
GCST011946_44	White matter hyperintensity volume	2.000000e-06
GCST011947_21	White matter hyperintensity volume	2.000000e-06
GCST011949_14	White matter hyperintensity volume (adjusted for hypertension)	4.000000e-06
GCST011950_11	White matter hyperintensity volume (adjusted for hypertension)	6.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0005665	white matter hyperintensity measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2321615 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 442,663 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL1491	AMLODIPINE	4	39,495
CHEMBL193	NIFEDIPINE	4	74,353
CHEMBL41	FLUOXETINE	4	62,368
CHEMBL54	HALOPERIDOL	4	60,883
CHEMBL558	MEXILETINE	4	15,463
CHEMBL631	PROPAFENONE	4	12,711
CHEMBL71	CHLORPROMAZINE	4	45,827
CHEMBL723	CARVEDILOL	4	30,225
CHEMBL726	FLUPHENAZINE	4	23,313
CHEMBL831	LOXAPINE	4	13,469
CHEMBL6066864	FLUPENTIXOL	3
CHEMBL23588	FLUFENAMIC ACID	2	34,797
CHEMBL28854	SIPATRIGINE	2	673

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6686529	Efficacy	3	sevoflurane	sedation

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6686529	KCNK2	3	2.50	1	sevoflurane

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Two-pore domain potassium channels (K_2P)

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
ONO-TR-772	Inhibition	7.82	pIC50
Cpd8l [PMID: 40040241]	Inhibition	6.1	pIC50
GI‐530159	Activator	6.05	pEC50
ONO-2920632	Activation	5.55	pEC50
BL-1249	Activator	5.26	pEC50
norfluoxetine	Inhibitor	5.05	pIC50
arachidonic acid	Activation	5.0	pEC50
LPS2336	Activation	4.93	pEC50

Binding affinities (BindingDB)

16 measured of 21 human assays (28 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CAS_53772-85-3	KI	0.2 nM
(S)-[(5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol	IC50	9 nM	US-9173935: Phospholipid drug analogs
cid_3396	KI	56 nM
I-NBP	EC50	60 nM
2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol;hydrochloride	KI	146 nM
CHEBI:2668	EC50	430 nM
Methoxy-acetic acid 2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl ester	EC50	500 nM
1-(1-(4,4-bis(4-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one	KI	650 nM
Niguldipine	EC50	750 nM
13-chloro-10-(4-methylpiperazin-1-yl)-2-oxa-9-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3,5,7,9,12,14-heptaene	KI	2460 nM
Chlorpromazine sulfoxide	EC50	2700 nM
2-(4-Methyl-piperazin-1-yl)-5-(2,3,5-trichloro-phenyl)-pyrimidin-4-ylamine(BW619C89)	EC50	4000 nM
Haldol	EC50	5500 nM
CHEBI:7565	EC50	8180 nM
1-((p-(2-(5-chloro-o-anisamido)ethyl)phenyl)sulfonyl)-3-cyclohexylurea	EC50	64000 nM
Bupivacaine	EC50	113000 nM

ChEMBL bioactivities

82 potent at pChembl≥5 of 112 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.17	IC50	67	nM	CHEMBL6171919
7.15	IC50	71	nM	CHEMBL3817944
6.96	IC50	110	nM	CHEMBL6175866
6.85	IC50	140	nM	CHEMBL6175206
6.75	IC50	180	nM	CHEMBL6173477
6.68	IC50	210	nM	CHEMBL6170812
6.58	IC50	260	nM	CHEMBL6171919
6.54	IC50	290	nM	CHEMBL6163118
6.40	IC50	400	nM	AMLODIPINE
6.37	IC50	430	nM	CHEMBL6171736
6.37	IC50	430	nM	AMLODIPINE
6.37	IC50	430	nM	CHEMBL1275655
6.37	IC50	430	nM	NIFEDIPINE
6.34	IC50	460	nM	CHEMBL6145471
6.27	IC50	540	nM	CHEMBL6165106
6.25	IC50	560	nM	CHEMBL6176406
6.25	IC50	560	nM	CHEMBL6172150
6.21	IC50	610	nM	CHEMBL6171453
6.09	IC50	810	nM	CHEMBL6173203
6.07	IC50	850	nM	CHEMBL6147409
6.04	IC50	910	nM	CHEMBL6166851
5.85	IC50	1400	nM	CHEMBL6168100
5.84	IC50	1450	nM	CHEMBL6176207
5.82	IC50	1520	nM	AMLODIPINE
5.80	IC50	1600	nM	CARVEDILOL
5.80	IC50	1600	nM	CHEMBL6173364
5.75	IC50	1800	nM	PIMOZIDE
5.75	IC50	1800	nM	HALOPERIDOL
5.75	IC50	1800	nM	LOXAPINE
5.75	IC50	1800	nM	Z-FLUPENTIXOL
5.74	IC50	1830	nM	CHEMBL6176207
5.70	IC50	2000	nM	FLUPENTIXOL
5.69	IC50	2060	nM	CHEMBL6165289
5.68	IC50	2110	nM	CHEMBL6176207
5.67	IC50	2120	nM	CHEMBL6175491
5.57	IC50	2700	nM	CHLORPROMAZINE
5.52	EC50	3000	nM	CHEMBL3818672
5.52	IC50	2990	nM	CHEMBL4742771
5.43	IC50	3730	nM	CHEMBL6173684
5.42	EC50	3800	nM	CHEMBL4776102
5.41	EC50	3910	nM	CHEMBL4552751
5.40	IC50	4000	nM	SIPATRIGINE
5.39	IC50	4100	nM	PROPAFENONE
5.39	IC50	4100	nM	MEXILETINE
5.39	IC50	4100	nM	BEPRIDIL
5.37	EC50	4300	nM	CHEMBL4747631
5.36	EC50	4400	nM	CHEMBL4780579
5.36	IC50	4350	nM	CHEMBL6176162
5.34	EC50	4600	nM	CHEMBL4795261
5.33	IC50	4700	nM	FLUPHENAZINE

PubChem BioAssay actives

46 with measured affinity, of 318 total; 40 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3R)-3-butyl-3H-2-benzofuran-1-one	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	0.0600	uM
(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-1-[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[(2S)-2-aminopropanoyl]pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoic acid	1307727: Inhibition of of TREK1 (unknown origin) expressed in whole COS7 cells assessed as reduction in channel currents in presence of 10 uM arachidonic acid	ic50	0.0710	uM
1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]piperidin-4-ol	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	0.1870	uM
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	0.2320	uM
Pimozide	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	0.3540	uM
Amlodipine	726094: Inhibition of TREK-1 (unknown origin)	ic50	0.4000	uM
[(1S,2S)-2-[2-[3-(1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-6-fluoro-1-propan-2-yl-3,4-dihydro-1H-naphthalen-2-yl] 2-methoxyacetate	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	0.5000	uM
5-O-[3-(4,4-diphenylpiperidin-1-yl)propyl] 3-O-methyl (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	0.7500	uM
Carvedilol	1307726: Inhibition of of human TREK1 expressed in HEK293 cells assessed as reduction in channel currents	ic50	1.6000	uM
2-[4-[(3E)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	2.0000	uM
2-[4-[(3Z)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol	1307728: Inhibition of of human TREK1 expressed in whole COS cells assessed as reduction in channel currents	ic50	2.0000	uM
1-[bis(4-fluorophenyl)methyl]-4-[(E)-3-phenylprop-2-enyl]piperazine	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	2.4800	uM
Chlorpromazine	1307728: Inhibition of of human TREK1 expressed in whole COS cells assessed as reduction in channel currents	ic50	2.7000	uM
3-(2-chloro-5-oxophenothiazin-10-yl)-N,N-dimethylpropan-1-amine	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	2.7000	uM
4-chloro-N’-(2-quinolin-2-ylsulfanylacetyl)benzohydrazide	1675884: Inhibition of human TREK1 at intermediate transition state expressed in CHO cells by whole-cell patch-clamp electrophysiological method	ic50	2.9900	uM
4-chloro-2-[[(E)-3-(4-pentylphenyl)prop-2-enoyl]amino]benzoic acid	1307710: Activation of human TREK1 expressed in CHO cells assessed as increase in channel currents at +50 mV relative to control	ec50	3.0000	uM
4,5-dimethyl-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]thiophene-3-carboxylic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	3.1000	uM
5-chloro-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]benzoic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	3.8000	uM
Quinine	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ic50	3.8500	uM
cis-(1S,3R)-3-[[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]carbamoyl]cyclopentane-1-carboxylic acid	1561371: Activation of recombinant human TREK1 W290A mutant expressed in HEK293T cells assessed as increase in K+ current amplitude by whole cell voltage clamp electrophysiological analysis	ec50	3.9100	uM
2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidin-4-amine	1307721: Inhibition of of human TREK1 expressed in HEK293 cells assessed as reversible current depression	ic50	4.0000	uM
4-bromo-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]benzoic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	4.3000	uM
4-chloro-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]benzoic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	4.4000	uM
5-(trifluoromethoxy)-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]benzoic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	4.6000	uM
Fluphenazine	1307728: Inhibition of of human TREK1 expressed in whole COS cells assessed as reduction in channel currents	ic50	4.7000	uM
1-[(4-propan-2-yloxyphenyl)methyl]-4-[[2-(trifluoromethyl)pyrrolo[2,3-b]pyridin-1-yl]methyl]piperidin-4-ol	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ic50	4.7000	uM
(7Z,10Z,13Z,16Z)-N-(2-hydroxyethyl)docosa-7,10,13,16-tetraenamide	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	5.1000	uM
N-[2-(2H-tetrazol-5-yl)phenyl]-5,6,7,8-tetrahydronaphthalen-1-amine	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	5.2000	uM
Haloperidol	1307728: Inhibition of of human TREK1 expressed in whole COS cells assessed as reduction in channel currents	ic50	5.5000	uM
Haloperidol Decanoate	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	5.5000	uM
5-bromo-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]benzoic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	5.9000	uM
5-bromo-4-fluoro-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]benzoic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	6.1000	uM
Propafenone	1307730: Inhibition of of human TREK1 expressed in CHO cells assessed as reduction in channel currents	ic50	7.6000	uM
Nifedipine	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	8.1800	uM
(3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine	1802150: TREK1 Assay from Article 10.1111/cbdd.12810: “Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.”	ec50	9.0000	uM
3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine	1307725: Inhibition of of human TREK1 expressed in tsA201 cells assessed as reduction in channel currents	ic50	9.0000	uM
5-fluoro-2-[[4-(trifluoromethylsulfanyl)benzoyl]amino]benzoic acid	1672908: Activation of human TREK1 by thallium flux mobilization assay	ec50	9.5000	uM
2,7-dichloro-9,9-dimethyl-10-[2-(2H-tetrazol-5-yl)ethyl]acridine	1307713: Activation of TREK1 (unknown origin) expressed in HEK293 cells assessed as increase in current density relative to control	ec50	9.7000	uM
2-ethoxy-N-[1-[3-(methylamino)phenyl]ethyl]-5-(2-methylpropanoylamino)benzamide	2093286: Inhibition of TREK-1 (unknown origin) by whole cell patch-clamp assay	ic50	10.0000	uM
N-[1-[3-(difluoromethoxy)phenyl]ethyl]-2-ethoxy-5-(2-methylpropanoylamino)benzamide	2093286: Inhibition of TREK-1 (unknown origin) by whole cell patch-clamp assay	ic50	10.0000	uM

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	decreases methylation	1
lead acetate	decreases expression	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
incobotulinumtoxinA	increases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Dasatinib	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Cadmium	decreases expression	1
Camptothecin	decreases response to substance	1
Copper	affects binding, decreases expression	1
Diltiazem	decreases reaction, increases transport	1
Flufenamic Acid	increases reaction, increases transport	1
Halothane	increases reaction, increases transport	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Mefenamic Acid	increases reaction, increases transport	1
Methapyrilene	affects methylation	1
Niflumic Acid	increases reaction, increases transport	1

ChEMBL screening assays

161 unique, capped per target: 161 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2327431	Binding	Inhibition of human TREK-1 expressed in HEK293 cells by patch-clamp technique	Ion channels as therapeutic targets: a drug discovery perspective. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_JQ47	h-TREK-1/HEK	Transformed cell line	Female
CVCL_SU06	HAP1 KCNK2 (-) 1	Cancer cell line	Male
CVCL_SU07	HAP1 KCNK2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.