KCNKI_HUMAN
ID KCNKI_HUMAN Reviewed; 384 AA.
AC Q7Z418; Q5SQQ8;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2003, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Potassium channel subfamily K member 18;
DE AltName: Full=TWIK-related individual potassium channel;
DE AltName: Full=TWIK-related spinal cord potassium channel;
GN Name=KCNK18; Synonyms=TRESK, TRIK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Spinal cord;
RX PubMed=12754259; DOI=10.1074/jbc.m206810200;
RA Sano Y., Inamura K., Miyake A., Mochizuki S., Kitada C., Yokoi H.,
RA Nozawa K., Okada H., Matsushime H., Furuichi K.;
RT "A novel two-pore domain K+ channel, TRESK, is localized in the spinal
RT cord.";
RL J. Biol. Chem. 278:27406-27412(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [3]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=15562060; DOI=10.1213/01.ane.0000136849.07384.44;
RA Liu C., Au J.D., Zou H.L., Cotten J.F., Yost C.S.;
RT "Potent activation of the human tandem pore domain K channel TRESK with
RT clinical concentrations of volatile anesthetics.";
RL Anesth. Analg. 99:1715-1722(2004).
RN [4]
RP MUTAGENESIS OF TYR-121.
RX PubMed=17962323; DOI=10.1113/jphysiol.2007.145649;
RA Dobler T., Springauf A., Tovornik S., Weber M., Schmitt A., Sedlmeier R.,
RA Wischmeyer E., Doring F.;
RT "TRESK two-pore-domain K+ channels constitute a significant component of
RT background potassium currents in murine dorsal root ganglion neurones.";
RL J. Physiol. (Lond.) 585:867-879(2007).
RN [5]
RP SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-70, AND MUTAGENESIS OF ASN-70
RP AND ASN-96.
RX PubMed=20006580; DOI=10.1016/j.bbrc.2009.12.056;
RA Egenberger B., Polleichtner G., Wischmeyer E., Doring F.;
RT "N-linked glycosylation determines cell surface expression of two-pore-
RT domain K+ channel TRESK.";
RL Biochem. Biophys. Res. Commun. 391:1262-1267(2010).
RN [6]
RP TISSUE SPECIFICITY, INVOLVEMENT IN MGR13, AND VARIANTS VAL-34 AND VAL-233.
RX PubMed=20871611; DOI=10.1038/nm.2216;
RA Lafreniere R.G., Cader M.Z., Poulin J.F., Andres-Enguix I., Simoneau M.,
RA Gupta N., Boisvert K., Lafreniere F., McLaughlan S., Dube M.P.,
RA Marcinkiewicz M.M., Ramagopalan S., Ansorge O., Brais B., Sequeiros J.,
RA Pereira-Monteiro J.M., Griffiths L.R., Tucker S.J., Ebers G., Rouleau G.A.;
RT "A dominant-negative mutation in the TRESK potassium channel is linked to
RT familial migraine with aura.";
RL Nat. Med. 16:1157-1160(2010).
CC -!- FUNCTION: Outward rectifying potassium channel. Produces rapidly
CC activating outward rectifier K(+) currents. May function as background
CC potassium channel that sets the resting membrane potential. Channel
CC activity is directly activated by calcium signal. Activated by the
CC G(q)-protein coupled receptor pathway. The calcium signal robustly
CC activates the channel via calcineurin, whereas the anchoring of 14-3-
CC 3/YWHAH interferes with the return of the current to the resting state
CC after activation. Inhibited also by arachidonic acid and other
CC naturally occurring unsaturated free fatty acids. Channel activity is
CC also enhanced by volatile anesthetics, such as isoflurane. Appears to
CC be the primary target of hydroxy-alpha-sanshool, an ingredient of
CC Schezuan pepper. May be involved in the somatosensory function with
CC special respect to pain sensation (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:12754259, ECO:0000269|PubMed:15562060}.
CC -!- SUBUNIT: Interacts with calcineurin. Interacts with YWHAH, in a
CC phosphorylation-dependent manner. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20006580};
CC Multi-pass membrane protein {ECO:0000269|PubMed:20006580}.
CC -!- TISSUE SPECIFICITY: Expressed specifically in dorsal root ganglion and
CC trigeminal ganglion neurons. Detected at low levels in spinal cord.
CC {ECO:0000269|PubMed:12754259, ECO:0000269|PubMed:15562060,
CC ECO:0000269|PubMed:20871611}.
CC -!- PTM: Phosphorylation of Ser-252 is required for the binding of 14-3-
CC 3eta/YWHAH. Calcineurin-mediated dephosphorylation of Ser-264 enhances
CC channel activity (By similarity). {ECO:0000250}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:20006580}.
CC -!- DISEASE: Migraine with or without aura 13 (MGR13) [MIM:613656]: A form
CC of migraine transmitted in an autosomal dominant pattern. Migraine is a
CC disabling symptom complex of periodic headaches, usually temporal and
CC unilateral. Headaches are often accompanied by irritability, nausea,
CC vomiting and photophobia, preceded by constriction of the cranial
CC arteries. The two major subtypes are common migraine (migraine without
CC aura) and classic migraine (migraine with aura). Classic migraine is
CC characterized by recurrent attacks of reversible neurological symptoms
CC (aura) that precede or accompany the headache. Aura may include a
CC combination of sensory disturbances, such as blurred vision,
CC hallucinations, vertigo, numbness and difficulty in concentrating and
CC speaking. {ECO:0000269|PubMed:20871611}. Note=The disease is caused by
CC variants affecting the gene represented in this entry. Susceptibility
CC to migraine has been shown to be conferred by a frameshift mutation
CC that segregates with the disorder in a large multigenerational family.
CC Migraine was associated with sensitivity to lights, sounds, and smells,
CC as well as nausea and occasional vomiting. Triggers included fatigue,
CC alcohol and bright lights. Mutations in KCNK18 are a rare cause of
CC migraine.
CC -!- MISCELLANEOUS: In contrast to its mouse ortholog, it is not regulated
CC by extracellular protons.
CC -!- SIMILARITY: Belongs to the two pore domain potassium channel (TC
CC 1.A.1.8) family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Throb - Issue 124 of
CC December 2010;
CC URL="https://web.expasy.org/spotlight/back_issues/124";
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DR EMBL; AB087138; BAC78527.1; -; mRNA.
DR EMBL; AL731557; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS7598.1; -.
DR RefSeq; NP_862823.1; NM_181840.1.
DR AlphaFoldDB; Q7Z418; -.
DR BioGRID; 130759; 28.
DR STRING; 9606.ENSP00000334650; -.
DR BindingDB; Q7Z418; -.
DR ChEMBL; CHEMBL2331042; -.
DR DrugCentral; Q7Z418; -.
DR GlyGen; Q7Z418; 1 site.
DR iPTMnet; Q7Z418; -.
DR PhosphoSitePlus; Q7Z418; -.
DR BioMuta; KCNK18; -.
DR DMDM; 74750072; -.
DR PaxDb; Q7Z418; -.
DR PeptideAtlas; Q7Z418; -.
DR PRIDE; Q7Z418; -.
DR ProteomicsDB; 69129; -.
DR Antibodypedia; 46272; 113 antibodies from 29 providers.
DR DNASU; 338567; -.
DR Ensembl; ENST00000334549.1; ENSP00000334650.1; ENSG00000186795.1.
DR GeneID; 338567; -.
DR KEGG; hsa:338567; -.
DR MANE-Select; ENST00000334549.1; ENSP00000334650.1; NM_181840.1; NP_862823.1.
DR UCSC; uc010qsr.2; human.
DR CTD; 338567; -.
DR DisGeNET; 338567; -.
DR GeneCards; KCNK18; -.
DR HGNC; HGNC:19439; KCNK18.
DR HPA; ENSG00000186795; Tissue enhanced (choroid).
DR MalaCards; KCNK18; -.
DR MIM; 613655; gene.
DR MIM; 613656; phenotype.
DR neXtProt; NX_Q7Z418; -.
DR OpenTargets; ENSG00000186795; -.
DR PharmGKB; PA134985465; -.
DR VEuPathDB; HostDB:ENSG00000186795; -.
DR eggNOG; KOG1418; Eukaryota.
DR GeneTree; ENSGT00700000104522; -.
DR HOGENOM; CLU_022504_5_3_1; -.
DR InParanoid; Q7Z418; -.
DR OMA; FCCTVIS; -.
DR OrthoDB; 774951at2759; -.
DR PhylomeDB; Q7Z418; -.
DR TreeFam; TF316115; -.
DR PathwayCommons; Q7Z418; -.
DR Reactome; R-HSA-1299344; TWIK-related spinal cord K+ channel (TRESK).
DR Reactome; R-HSA-5576886; Phase 4 - resting membrane potential.
DR SignaLink; Q7Z418; -.
DR SIGNOR; Q7Z418; -.
DR BioGRID-ORCS; 338567; 7 hits in 1054 CRISPR screens.
DR GeneWiki; KCNK18; -.
DR GenomeRNAi; 338567; -.
DR Pharos; Q7Z418; Tclin.
DR PRO; PR:Q7Z418; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q7Z418; protein.
DR Bgee; ENSG00000186795; Expressed in nucleus accumbens and 5 other tissues.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0015269; F:calcium-activated potassium channel activity; IEA:Ensembl.
DR GO; GO:0015271; F:outward rectifier potassium channel activity; IDA:BHF-UCL.
DR GO; GO:0022841; F:potassium ion leak channel activity; IBA:GO_Central.
DR GO; GO:0071467; P:cellular response to pH; IDA:BHF-UCL.
DR GO; GO:0097623; P:potassium ion export across plasma membrane; IDA:BHF-UCL.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0006813; P:potassium ion transport; IDA:UniProtKB.
DR GO; GO:0030322; P:stabilization of membrane potential; IBA:GO_Central.
DR InterPro; IPR003280; 2pore_dom_K_chnl.
DR InterPro; IPR013099; K_chnl_dom.
DR PANTHER; PTHR11003; PTHR11003; 1.
DR Pfam; PF07885; Ion_trans_2; 2.
DR PRINTS; PR01333; 2POREKCHANEL.
PE 1: Evidence at protein level;
KW Cell membrane; Glycoprotein; Ion channel; Ion transport; Membrane;
KW Phosphoprotein; Potassium; Potassium channel; Potassium transport;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..384
FT /note="Potassium channel subfamily K member 18"
FT /id="PRO_0000312500"
FT TOPO_DOM 1..23
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 24..44
FT /note="Helical"
FT /evidence="ECO:0000255"
FT INTRAMEM 103..129
FT /note="Pore-forming; Name=Pore-forming 1"
FT /evidence="ECO:0000255"
FT TRANSMEM 130..148
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 149..280
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 281..301
FT /note="Helical"
FT /evidence="ECO:0000255"
FT INTRAMEM 314..328
FT /note="Pore-forming; Name=Pore-forming 2"
FT /evidence="ECO:0000255"
FT TRANSMEM 335..355
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 356..384
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 200..205
FT /note="Interaction with calcineurin"
FT /evidence="ECO:0000250"
FT REGION 249..254
FT /note="Interaction with YWHAH"
FT /evidence="ECO:0000250"
FT SITE 96
FT /note="Not glycosylated"
FT MOD_RES 252
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6VV64"
FT MOD_RES 264
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6VV64"
FT CARBOHYD 70
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:20006580"
FT VARIANT 34
FT /note="A -> V"
FT /evidence="ECO:0000269|PubMed:20871611"
FT /id="VAR_064027"
FT VARIANT 58
FT /note="F -> Y (in dbSNP:rs3909165)"
FT /id="VAR_037521"
FT VARIANT 198
FT /note="A -> G (in dbSNP:rs363359)"
FT /id="VAR_037522"
FT VARIANT 231
FT /note="S -> P (in dbSNP:rs363315)"
FT /id="VAR_037523"
FT VARIANT 233
FT /note="A -> V (in dbSNP:rs363360)"
FT /evidence="ECO:0000269|PubMed:20871611"
FT /id="VAR_037524"
FT VARIANT 255
FT /note="E -> K (in dbSNP:rs3026042)"
FT /id="VAR_037525"
FT VARIANT 346
FT /note="V -> I (in dbSNP:rs12247136)"
FT /id="VAR_037526"
FT MUTAGEN 70
FT /note="N->Q: Strongly reduced current amplitude and
FT localization to cell membrane. Strongly reduced current
FT amplitude and localization to cell membrane; when
FT associated with Q-96."
FT /evidence="ECO:0000269|PubMed:20006580"
FT MUTAGEN 96
FT /note="N->Q: Strongly reduced current amplitude and
FT localization to cell membrane. Strongly reduced current
FT amplitude and localization to cell membrane; when
FT associated with Q-70."
FT /evidence="ECO:0000269|PubMed:20006580"
FT MUTAGEN 121
FT /note="Y->H: Restores sensitivity to extracellular
FT protons."
FT /evidence="ECO:0000269|PubMed:17962323"
SQ SEQUENCE 384 AA; 43671 MW; 5D0B544F815ACB1C CRC64;
MEVSGHPQAR RCCPEALGKL FPGLCFLCFL VTYALVGAVV FSAIEDGQVL VAADDGEFEK
FLEELCRILN CSETVVEDRK QDLQGHLQKV KPQWFNRTTH WSFLSSLFFC CTVFSTVGYG
YIYPVTRLGK YLCMLYALFG IPLMFLVLTD TGDILATILS TSYNRFRKFP FFTRPLLSKW
CPKSLFKKKP DPKPADEAVP QIIISAEELP GPKLGTCPSR PSCSMELFER SHALEKQNTL
QLPPQAMERS NSCPELVLGR LSYSIISNLD EVGQQVERLD IPLPIIALIV FAYISCAAAI
LPFWETQLDF ENAFYFCFVT LTTIGFGDTV LEHPNFFLFF SIYIIVGMEI VFIAFKLVQN
RLIDIYKNVM LFFAKGKFYH LVKK
