KCNK18

Summary

KCNK18 (potassium two pore domain channel subfamily K member 18, HGNC:19439) is a protein-coding gene on chromosome 10q25.3, encoding Potassium channel subfamily K member 18 (Q7Z418). K(+) channel that conducts outward and inward rectifying currents at depolarized and hyperpolarized membrane potentials, respectively.

Potassium channels play a role in many cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. This gene encodes a member of the superfamily of potassium channel proteins containing two pore-forming P domains and the encoded protein functions as an outward rectifying potassium channel. A mutation in this gene has been found to be associated with migraine with aura.

Source: NCBI Gene 338567 — RefSeq curated summary.

At a glance

• Gene–disease (curated): migraine, with or without aura, susceptibility to, 13 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 100 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes
• MANE Select transcript: NM_181840

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19439
Approved symbol	KCNK18
Name	potassium two pore domain channel subfamily K member 18
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	K2p18.1, TRESK-2, TRESK2, TRESK, TRIK
Ensembl gene	ENSG00000186795
Ensembl biotype	protein_coding
OMIM	613655
Entrez	338567

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000334549, ENST00000850990

RefSeq mRNA: 1 — MANE Select: NM_181840 NM_181840

CCDS: CCDS7598

Canonical transcript exons

ENST00000334549 — 3 exons

Exon	Start	End
ENSE00001336458	117201159	117201287
ENSE00004283167	117209497	117210299
ENSE00004283168	117197489	117197711

Expression profiles

Bgee: expression breadth broad, 11 present calls, max score 40.39.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	40.39	gold quality
caudate nucleus	UBERON:0001873	37.99	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
prefrontal cortex	UBERON:0000451	36.89	gold quality
granulocyte	CL:0000094	36.84	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
frontal cortex	UBERON:0001870	33.06	silver quality
bone marrow	UBERON:0002371	32.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
hypothalamus	UBERON:0001898	30.80	gold quality
primary visual cortex	UBERON:0002436	30.75	gold quality
cerebral cortex	UBERON:0000956	30.09	silver quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
cortex of kidney	UBERON:0001225	29.38	gold quality
liver	UBERON:0002107	28.85	gold quality
brain	UBERON:0000955	28.30	silver quality
duodenum	UBERON:0002114	28.14	gold quality
anterior cingulate cortex	UBERON:0009835	28.09	silver quality
urinary bladder	UBERON:0001255	27.85	gold quality
leukocyte	CL:0000738	27.83	gold quality
lymph node	UBERON:0000029	27.57	gold quality
right frontal lobe	UBERON:0002810	27.35	gold quality
monocyte	CL:0000576	27.24	gold quality
tonsil	UBERON:0002372	27.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.82

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 24)

• TRESK is a novel two-pore domain K+ channel that may set the resting membrane potential of cells in the spinal cord (PMID:12754259)
• TRESK is activated by increased cytoplasmic calcium concentration, calcineurin being involved in the regulation; Serine 276 was identified as the major functional target of calcineurin in TRESK (PMID:14981085)
• TRESK-2 is a functional member of the K(2P) channel family and contributes to the background K+ conductance in many types of cells [TRESK-2] (PMID:15123670)
• Because 14-3-3 proteins are ubiquitous, they are expected to control the duration of calcineurin-mediated TRESK activation in all the cell types that express the channel, depending on the phosphorylation state of serine 264. (PMID:18397886)
• background K+ currents expressed in Jurkat cells are mediated by TRESK channels (PMID:18506476)
• single residue of TRESK was found to be glycosylated upon heterologous expression. Signals of the N-glycosylation mutants were reduced by >50% because of inadequate surface expression of the channel. (PMID:20006580)
• a role for TRESK in the pathogenesis of typical migraine with aura. (PMID:20871611)
• A frameshift mutation in the two-pore potassium channel protein TRESK is linked to migraine pathogenesis. (Review) (PMID:21855646)
• dominant-negative mutation of human TRESK was found to be linked to migraine with aura in a large pedigree. It is hoped that future TRESK agonists may prevent or ameliorate the debilitating symptoms of migraine. (PMID:22115960)
• T cell lymphoblastic leukemias/lymphomas express TRESK protein. (PMID:23541583)
• No association was observed for three polymorphisms in the KCNK18 gene with migraine phenotype or with any haplotypes. (PMID:23911303)
• Migraine-associated TRESK mutation, but not the C110R variant, reduces the endogenous TRESK currents to a degree that affects trigeminal ganglion neuron excitability (PMID:24805079)
• This study reveals new pharmacological modulators of K2P18.1 activity useful in dissecting native K2P18.1 function (PMID:24972239)
• LQLP site is a fundamental determinant of the calcium-sensitivity of human TRESK. (PMID:25202008)
• Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura (PMID:25324165)
• The presence of SCN1A mutations and absence of mutations in ATP1A2 or CACNA1A suggest that the Polish patients represent FHM type 3. (PMID:26747084)
• both human and rat TRESK contain potential anionic phospholipid binding sites (apbs) in the large cytoplasmic loop, but only the human channel is able to bind to multilamellar vesicles (MLVs), enriched with anionic phospholipids, suggesting an electrostatically mediated interaction. (PMID:30039335)
• Results provide evidence that the activation of novel-type PKC results in the slow (indirect) dephosphorylation of TRESK at the regulatory residue S264 in a calcineurin-independent manner. (PMID:30992311)
• Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. (PMID:31742594)
• Altered functional properties of a missense variant in the TRESK K(+) channel (KCNK18) associated with migraine and intellectual disability. (PMID:32394190)
• The Background K(+) Channel TRESK in Sensory Physiology and Pain. (PMID:32717813)
• TRESK background potassium channel modifies the TRPV1-mediated nociceptor excitability in sensory neurons. (PMID:33525904)
• KCNK18 Biallelic Variants Associated with Intellectual Disability and Neurodevelopmental Disorders Alter TRESK Channel Activity. (PMID:34199759)
• Further evidence of biallelic variants in KCNK18 as a cause of intellectual disability and epilepsy with febrile seizure plus. (PMID:37195340)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnk18	ENSDARG00000057049
mus_musculus	Kcnk18	ENSMUSG00000040901
rattus_norvegicus	Kcnk18	ENSRNOG00000032706
drosophila_melanogaster	Ork1	FBGN0017561
drosophila_melanogaster	sand	FBGN0033257
drosophila_melanogaster	Task7	FBGN0037690
drosophila_melanogaster	Task6	FBGN0038165
drosophila_melanogaster	CG10864	FBGN0038621
drosophila_melanogaster	CG34396	FBGN0085425
drosophila_melanogaster	CG42340	FBGN0259242
drosophila_melanogaster	CG42594	FBGN0260971
drosophila_melanogaster	CG43155	FBGN0262685
caenorhabditis_elegans		WBGENE00001190

Paralogs (14): KCNK2 (ENSG00000082482), 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)

Protein

Protein identifiers

Potassium channel subfamily K member 18 — Q7Z418 (reviewed: Q7Z418)

Alternative names: TWIK-related individual potassium channel, TWIK-related spinal cord potassium channel

All UniProt accessions (1): Q7Z418

UniProt curated annotations — full annotation on UniProt →

Function. K(+) channel that conducts outward and inward rectifying currents at depolarized and hyperpolarized membrane potentials, respectively. The outward rectifying currents are voltage-dependent, coupled to K(+) electrochemical gradient across the membrane, whereas the inward currents can be induced in response to activation of Ca(2+)-mobilizing receptors. Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties. In trigeminal ganglia sensory neurons, the heterodimers of KCNK18/TRESK and KCNK2/TREK-1 or KCNK10/TREK-2 inhibit 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. In thymocytes, conducts K(+) currents upon T cell receptor (TCR) signaling leading to sustained Ca(2+) influx and NF-kappa-B activation, FOXP3 transcription and positive selection of regulatory T cell (Treg) progenitor subsets. Appears to mediate the analgesics effects of hydroxy-alpha-sanshool, a metabolite naturally present in Schezuan pepper and other Xanthoxylum plants.

Subunit / interactions. Homodimer. Heterodimer with KCNK2. Heterodimer with KCNK10. Interacts with calcineurin. Interacts with YWHAH, in a phosphorylation-dependent manner.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in dorsal root ganglion and trigeminal ganglion neurons. Detected at low levels in spinal cord. Expressed in regulatory T cells (at protein level).

Post-translational modifications. N-glycosylated. Phosphorylation of Ser-264 is required for the binding of 14-3-3eta/YWHAH. Calcineurin-mediated dephosphorylation enhances channel activity.

Disease relevance. Migraine with or without aura 13 (MGR13) [MIM:613656] A form of migraine transmitted in an autosomal dominant pattern. Migraine is a disabling symptom complex of periodic headaches, usually temporal and unilateral. Headaches are often accompanied by irritability, nausea, vomiting and photophobia, preceded by constriction of the cranial arteries. The two major subtypes are common migraine (migraine without aura) and classic migraine (migraine with aura). Classic migraine is characterized by recurrent attacks of reversible neurological symptoms (aura) that precede or accompany the headache. Aura may include a combination of sensory disturbances, such as blurred vision, hallucinations, vertigo, numbness and difficulty in concentrating and speaking. The disease is caused by variants affecting the gene represented in this entry. Susceptibility to migraine has been shown to be conferred by a frameshift mutation that segregates with the disorder in a large multigenerational family. Migraine was associated with sensitivity to lights, sounds, and smells, as well as nausea and occasional vomiting. Triggers included fatigue, alcohol and bright lights. Mutations in KCNK18 are a rare cause of migraine.

Activity regulation. Activated by volatile anesthetics but inhibited by amide local anesthetics. Inhibited by Ba(2+) ions. Inhibited by free polyunsaturated fatty acids. Channel conductance is sensitive to intracellular pH, it decreases at acidic pH and increases at basic pH. In contrast to its mouse ortholog, it is not regulated by extracellular protons. Insensitive to changes in temperature.

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.

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

RefSeq proteins (1): NP_862823* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003280	2pore_dom_K_chnl	Family
IPR013099	K_chnl_dom	Domain

Pfam: PF07885

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (38 total): sequence variant 9, binding site 7, region of interest 4, transmembrane region 4, topological domain 3, mutagenesis site 3, modified residue 2, intramembrane region 2, chain 1, site 1, glycosylation site 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z418-F1	70.04	0.23

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): 96 (not glycosylated)

Ligand- & substrate-binding residues (7): 116; 116; 117; 117; 118; 118; 119

Post-translational modifications (2): 252, 264

Disulfide bonds (1): 66

Glycosylation sites (1): 70

Mutagenesis-validated functional residues (3):

Position	Phenotype
70	strongly reduced current amplitude and localization to cell membrane. strongly reduced current amplitude and localizatio
96	strongly reduced current amplitude and localization to cell membrane. strongly reduced current amplitude and localizatio
121	restores sensitivity to extracellular protons.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1299344	TWIK-related spinal cord K+ channel (TRESK)
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: 87 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, REACTOME_TANDEM_PORE_DOMAIN_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, HNF1_Q6, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_CD4_POSITIVE_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_LYMPHOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_CD4_POSITIVE_ALPHA_BETA_T_CELL_ACTIVATION, TGACATY_UNKNOWN

GO Biological Process (7): potassium ion transport (GO:0006813), regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation (GO:0032829), cellular response to pH (GO:0071467), potassium ion transmembrane transport (GO:0071805), potassium ion export across plasma membrane (GO:0097623), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (5): calcium-activated potassium channel activity (GO:0015269), outward rectifier potassium channel activity (GO:0015271), potassium ion leak channel activity (GO:0022841), metal ion binding (GO:0046872), potassium channel activity (GO:0005267)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

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	2
metal ion transport	1
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1
regulation of CD4-positive, alpha-beta T cell differentiation	1
regulation of regulatory T cell differentiation	1
response to pH	1
cellular response to abiotic stimulus	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
potassium ion transmembrane transport	1
export across plasma membrane	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
calcium-activated cation channel activity	1
voltage-gated potassium channel activity	1
leak channel activity	1
cation binding	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

680 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNK18	KRT76	Q01546	987
KCNK18	ATP1A2	P50993	806
KCNK18	SCN1A	P35498	764
KCNK18	KCNK13	Q9HB14	756
KCNK18	KCNK12	Q9HB15	705
KCNK18	CACNA1A	P78510	705
KCNK18	KCNK7	Q9Y2U2	700
KCNK18	KCNK17	Q96T54	697
KCNK18	KCNK3	O14649	613
KCNK18	KCNK10	P57789	569
KCNK18	EDNRA	P25101	556
KCNK18	YWHAH	Q04917	522
KCNK18	TRPV1	Q8NER1	506
KCNK18	AKAP5	P24588	501
KCNK18	TRPM8	Q7Z2W7	491

IntAct

2 interactions, top by confidence:

A	B	Type	Score
KCNK18	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (29): PPP3R1 (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), IFNGR1 (Affinity Capture-MS), PCNXL3 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), TMEM179B (Affinity Capture-MS), RMDN3 (Affinity Capture-MS), MFAP3 (Affinity Capture-MS), ADIPOR1 (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), FUT8 (Affinity Capture-MS), LRRC8A (Affinity Capture-MS), PTPRD (Affinity Capture-MS), ACVR1 (Affinity Capture-MS), OCIAD1 (Affinity Capture-MS)

ESM2 similar proteins: A2A259, A5X5Y0, H2Q5A1, O46547, O70212, O95264, O97741, P01906, P01909, P02713, P02715, P02716, P04758, P04759, P04760, P07510, P09660, P09690, P11230, P13536, P18916, P20782, P23979, P25109, P25110, P35563, P37088, P37089, P46098, P55270, P78334, Q04844, Q07001, Q14246, Q5Y4N8, Q60HE8, Q61180, Q61549, Q70Z44, Q7Z418

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

2 interactions.

A	Effect	B	Mechanism
PKA	“down-regulates activity”	KCNK18	phosphorylation
YWHAH	“down-regulates activity”	KCNK18	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	58
Likely benign	25
Benign	10

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1802569	NM_181840.1(KCNK18):c.487T>G (p.Tyr163Asp)	Pathogenic
1810423	NM_181840.1(KCNK18):c.499C>T (p.Arg167Ter)	Pathogenic
3713509	NM_181840.1(KCNK18):c.755C>T (p.Ser252Leu)	Likely pathogenic

SpliceAI

359 predictions. Top by Δscore:

Variant	Effect	Δscore
10:117197707:AACAG:A	donor_gain	1.0000
10:117197708:ACAG:A	donor_gain	1.0000
10:117197709:CAG:C	donor_gain	1.0000
10:117197710:AG:A	donor_gain	1.0000
10:117197711:GG:G	donor_gain	1.0000
10:117197712:G:GG	donor_gain	1.0000
10:117201157:A:AG	acceptor_gain	1.0000
10:117201157:AGT:A	acceptor_gain	1.0000
10:117201158:G:GA	acceptor_gain	1.0000
10:117201158:GT:G	acceptor_gain	1.0000
10:117201158:GTG:G	acceptor_gain	1.0000
10:117209491:TTTCA:T	acceptor_loss	1.0000
10:117209492:TTCAG:T	acceptor_loss	1.0000
10:117209494:CA:C	acceptor_loss	1.0000
10:117209495:A:AG	acceptor_gain	1.0000
10:117209495:AG:A	acceptor_gain	1.0000
10:117209496:G:GG	acceptor_gain	1.0000
10:117209496:GG:G	acceptor_gain	1.0000
10:117209496:GGC:G	acceptor_gain	1.0000
10:117209496:GGCT:G	acceptor_gain	1.0000
10:117209496:GGCTA:G	acceptor_gain	1.0000
10:117197709:CAGGT:C	donor_gain	0.9900
10:117197710:AGGTA:A	donor_gain	0.9900
10:117201076:G:GT	donor_gain	0.9900
10:117201076:G:T	donor_gain	0.9900
10:117201158:GTGGT:G	acceptor_gain	0.9900
10:117201053:C:T	donor_gain	0.9800
10:117201154:TCCA:T	acceptor_loss	0.9800
10:117201155:CCA:C	acceptor_loss	0.9800
10:117201156:CA:C	acceptor_loss	0.9800

AlphaMissense

2536 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:117201278:A:C	S115R	0.985
10:117201280:C:A	S115R	0.985
10:117201280:C:G	S115R	0.985
10:117210037:C:A	A298D	0.968
10:117197609:T:C	F41L	0.964
10:117197611:C:A	F41L	0.964
10:117197611:C:G	F41L	0.964
10:117210096:T:C	F318L	0.957
10:117210098:T:A	F318L	0.957
10:117210098:T:G	F318L	0.957
10:117201260:T:C	F109L	0.955
10:117201262:C:A	F109L	0.955
10:117201262:C:G	F109L	0.955
10:117201265:C:G	C110W	0.954
10:117209563:G:A	G140D	0.953
10:117201263:T:C	C110R	0.949
10:117210090:T:C	F316L	0.948
10:117210092:C:A	F316L	0.948
10:117210092:C:G	F316L	0.948
10:117210093:T:C	C317R	0.948
10:117210183:G:A	G347R	0.946
10:117210183:G:C	G347R	0.946
10:117201264:G:A	C110Y	0.942
10:117210120:T:C	F326L	0.941
10:117210122:T:A	F326L	0.941
10:117210122:T:G	F326L	0.941
10:117210095:C:G	C317W	0.940
10:117209569:C:G	P142R	0.938
10:117210106:T:C	L321P	0.937
10:117210030:T:C	C296R	0.935

dbSNP variants (sampled 300 via entrez): RS1000675361 (10:117201799 T>C), RS1000708940 (10:117208793 T>C,G), RS1000763471 (10:117198564 G>C,T), RS1001066806 (10:117210388 C>A,G), RS1001077682 (10:117209988 C>A,G,T), RS1001110413 (10:117197365 C>A,G,T), RS1001256001 (10:117207984 T>C,G), RS1001285746 (10:117208174 C>A), RS1001452830 (10:117196283 A>T), RS1001567251 (10:117196550 G>C,T), RS1001650613 (10:117198245 G>C), RS1001809060 (10:117202530 C>T), RS1001822777 (10:117203549 A>G), RS1002107002 (10:117203426 G>A), RS1002107200 (10:117203814 G>A,T)

Disease associations

OMIM: gene MIM:613655 | disease phenotypes: MIM:613656, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
migraine, with or without aura, susceptibility to, 13	Strong	Autosomal dominant

Mondo (4): migraine, with or without aura, susceptibility to, 13 (MONDO:0013344), Parkinson disease (MONDO:0005180), parkinsonian disorder (MONDO:0021095), vascular parkinsonism (MONDO:0956980)

Orphanet (1): NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002077	Migraine with aura
HP:0002083	Migraine without aura

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_66	Body mass index	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331042 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.22	EC50	6000	nM	CHEMBL1417584

PubChem BioAssay actives

1 with measured affinity, of 28 total; 1 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
N-[2-(2H-tetrazol-5-yl)phenyl]-5,6,7,8-tetrahydronaphthalen-1-amine	1321964: Activation of human TRESK channel relative to control	ec50	6.0000	uM

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Potassium	decreases reaction, increases transport	2
triethanolamine	decreases reaction, increases transport	1
sodium arsenite	increases expression	1
sanshool	affects response to substance, decreases reaction, increases transport, decreases activity	1
Arsenic	affects methylation	1
Barium	decreases reaction, increases transport	1
Benzo(a)pyrene	increases methylation	1
Glyburide	decreases reaction, increases transport	1
Lidocaine	decreases reaction, increases transport	1
Propafenone	increases transport, decreases reaction	1
Quinidine	decreases reaction, increases transport	1
Quinine	decreases reaction, increases transport	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

9 unique, capped per target: 7 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3861237	Binding	Activation of human TRESK channel expressed in HEK293 cells assessed as induction of channel current by whole cell patch clamp assay	Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K2P18.1. — Bioorg Med Chem Lett
CHEMBL3861239	ADMET	Channel blocking activity at human TRESK channel	Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K2P18.1. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0YJ	B’SYS HEK 293 K2P18.1	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients
NCT00642356	PHASE4	TERMINATED	Carbidopa/Levodopa/Entacapone Versus Immediate Release (IR) Carbidopa/Levodopa on Non-motor Symptoms in Patients With Idiopathic Parkinson’s Disease and Demonstrating Non-motor Symptoms of Wearing Off
NCT00646204	PHASE4	COMPLETED	Namenda (Memantine) for Non-motor Symptoms in Parkinson’s Disease