ID   KCNKI_MOUSE             Reviewed;         394 AA.
AC   Q6VV64; Q1LZJ5; Q1LZM8; Q3MI50; Q3MI51;
DT   04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2004, sequence version 1.
DT   27-MAR-2024, entry version 147.
DE   RecName: Full=Potassium channel subfamily K member 18;
DE   AltName: Full=Two-pore-domain potassium channel TRESK;
GN   Name=Kcnk18; Synonyms=Tresk-2, Tresk2;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MUTAGENESIS OF SER-276,
RP   PHOSPHORYLATION AT SER-276, AND TISSUE SPECIFICITY.
RC   STRAIN=NMRI; TISSUE=Cerebellum;
RX   PubMed=14981085; DOI=10.1074/jbc.m312229200;
RA   Czirjak G., Toth Z.E., Enyedi P.;
RT   "The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic
RT   calcium signal through calcineurin.";
RL   J. Biol. Chem. 279:18550-18558(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND FUNCTION.
RC   STRAIN=BALB/cJ; TISSUE=Spinal cord;
RX   PubMed=16192517; DOI=10.1213/01.ane.0000168447.87557.5a;
RA   Keshavaprasad B., Liu C., Au J.D., Kindler C.H., Cotten J.F., Yost C.S.;
RT   "Species-specific differences in response to anesthetics and other
RT   modulators by the K2P channel TRESK.";
RL   Anesth. Analg. 101:1042-1049(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Egg;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   INTERACTION WITH CALCINEURIN.
RX   PubMed=16569637; DOI=10.1074/jbc.m602495200;
RA   Czirjak G., Enyedi P.;
RT   "Targeting of calcineurin to an NFAT-like docking site is required for the
RT   calcium-dependent activation of the background K+ channel, TRESK.";
RL   J. Biol. Chem. 281:14677-14682(2006).
RN   [6]
RP   TISSUE SPECIFICITY, AND MUTAGENESIS OF HIS-132.
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   [7]
RP   INTERACTION WITH YWHAH, MUTAGENESIS OF SER-264, AND PHOSPHORYLATION AT
RP   SER-264.
RX   PubMed=18397886; DOI=10.1074/jbc.m800712200;
RA   Czirjak G., Vuity D., Enyedi P.;
RT   "Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK
RT   regulation.";
RL   J. Biol. Chem. 283:15672-15680(2008).
RN   [8]
RP   FUNCTION.
RX   PubMed=18568022; DOI=10.1038/nn.2143;
RA   Bautista D.M., Sigal Y.M., Milstein A.D., Garrison J.L., Zorn J.A.,
RA   Tsuruda P.R., Nicoll R.A., Julius D.;
RT   "Pungent agents from Szechuan peppers excite sensory neurons by inhibiting
RT   two-pore potassium channels.";
RL   Nat. Neurosci. 11:772-779(2008).
RN   [9]
RP   SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-83, AND MUTAGENESIS OF ASN-83.
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   [10]
RP   TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
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. {ECO:0000269|PubMed:14981085,
CC       ECO:0000269|PubMed:16192517, ECO:0000269|PubMed:18568022}.
CC   -!- SUBUNIT: Interacts with calcineurin. Interacts with YWHAH, in a
CC       phosphorylation-dependent manner. {ECO:0000269|PubMed:16569637,
CC       ECO:0000269|PubMed:18397886}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20006580};
CC       Multi-pass membrane protein {ECO:0000269|PubMed:20006580}.
CC   -!- TISSUE SPECIFICITY: Detected in brain cortex, cerebellum, dorsal root
CC       ganglion, spinal cord and testis. High expression in trigeminal
CC       ganglion, also expressed in autonomic nervous system ganglia such as
CC       the stellate ganglion and paravertebral sympathetic ganglia. Expressed
CC       in all adult spinal cord and brain regions, with slightly higher
CC       expression in thalamus, hypothalamus, hippocampus and posterior corte
CC       (at protein level). In non-neuronal tissues, substantial expression
CC       found in lung and heart and weal expression in liver, testis, kidney,
CC       small intestine and spleen. {ECO:0000269|PubMed:14981085,
CC       ECO:0000269|PubMed:16192517, ECO:0000269|PubMed:17962323,
CC       ECO:0000269|PubMed:20871611}.
CC   -!- DEVELOPMENTAL STAGE: Expression appears in trigeminal ganglion and
CC       dorsal root ganglia from 15.5 dpc and increased through 18 dpc to reach
CC       a peak in newborn mouse postnatal day 1. {ECO:0000269|PubMed:20871611}.
CC   -!- PTM: Phosphorylation of Ser-264 is required for the binding of 14-3-
CC       3eta/YWHAH. Calcineurin-mediated dephosphorylation of Ser-276 enhances
CC       channel activity. {ECO:0000269|PubMed:14981085,
CC       ECO:0000269|PubMed:18397886}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:20006580}.
CC   -!- MISCELLANEOUS: Regulated by extracellular protons whereas human
CC       ortholog is not. His-132 is responsible for proton-dependent specific
CC       activity.
CC   -!- SIMILARITY: Belongs to the two pore domain potassium channel
CC       (TC 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; AY325301; AAQ91836.1; -; mRNA.
DR   EMBL; AY542902; AAS48426.1; -; mRNA.
DR   EMBL; AK139600; BAE24080.1; -; mRNA.
DR   EMBL; AK162136; BAE36746.1; -; mRNA.
DR   EMBL; BC104132; AAI04133.1; -; mRNA.
DR   EMBL; BC104133; AAI04134.1; -; mRNA.
DR   EMBL; BC115705; AAI15706.1; -; mRNA.
DR   EMBL; BC115887; AAI15888.1; -; mRNA.
DR   EMBL; BC127136; AAI27137.1; -; mRNA.
DR   EMBL; BC127137; AAI27138.1; -; mRNA.
DR   CCDS; CCDS29934.1; -.
DR   RefSeq; NP_997144.1; NM_207261.3.
DR   AlphaFoldDB; Q6VV64; -.
DR   ELM; Q6VV64; -.
DR   IntAct; Q6VV64; 1.
DR   MINT; Q6VV64; -.
DR   STRING; 10090.ENSMUSP00000065713; -.
DR   ChEMBL; CHEMBL5169168; -.
DR   TCDB; 1.A.1.18.1; the voltage-gated ion channel (vic) superfamily.
DR   GlyCosmos; Q6VV64; 1 site, No reported glycans.
DR   GlyGen; Q6VV64; 1 site.
DR   iPTMnet; Q6VV64; -.
DR   PhosphoSitePlus; Q6VV64; -.
DR   PaxDb; 10090-ENSMUSP00000065713; -.
DR   ABCD; Q6VV64; 1 sequenced antibody.
DR   Antibodypedia; 46272; 125 antibodies from 29 providers.
DR   DNASU; 332396; -.
DR   Ensembl; ENSMUST00000065204.8; ENSMUSP00000065713.7; ENSMUSG00000040901.9.
DR   GeneID; 332396; -.
DR   KEGG; mmu:332396; -.
DR   UCSC; uc008ibh.1; mouse.
DR   AGR; MGI:2685627; -.
DR   CTD; 338567; -.
DR   MGI; MGI:2685627; Kcnk18.
DR   VEuPathDB; HostDB:ENSMUSG00000040901; -.
DR   eggNOG; KOG1418; Eukaryota.
DR   GeneTree; ENSGT00700000104522; -.
DR   HOGENOM; CLU_022504_5_3_1; -.
DR   InParanoid; Q6VV64; -.
DR   OMA; RWSSCPE; -.
DR   OrthoDB; 2903084at2759; -.
DR   PhylomeDB; Q6VV64; -.
DR   TreeFam; TF316115; -.
DR   Reactome; R-MMU-1299344; TWIK-related spinal cord K+ channel (TRESK).
DR   Reactome; R-MMU-5576886; Phase 4 - resting membrane potential.
DR   BioGRID-ORCS; 332396; 2 hits in 75 CRISPR screens.
DR   PRO; PR:Q6VV64; -.
DR   Proteomes; UP000000589; Chromosome 19.
DR   RNAct; Q6VV64; Protein.
DR   Bgee; ENSMUSG00000040901; Expressed in animal zygote and 4 other cell types or tissues.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0015269; F:calcium-activated potassium channel activity; IDA:UniProtKB.
DR   GO; GO:0015271; F:outward rectifier potassium channel activity; ISO:MGI.
DR   GO; GO:0022841; F:potassium ion leak channel activity; IBA:GO_Central.
DR   GO; GO:0071467; P:cellular response to pH; ISO:MGI.
DR   GO; GO:0097623; P:potassium ion export across plasma membrane; ISO:MGI.
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   Gene3D; 1.10.287.70; -; 1.
DR   InterPro; IPR003280; 2pore_dom_K_chnl.
DR   InterPro; IPR003092; 2pore_dom_K_chnl_TASK.
DR   InterPro; IPR013099; K_chnl_dom.
DR   PANTHER; PTHR11003:SF291; POTASSIUM CHANNEL SUBFAMILY K MEMBER 18; 1.
DR   PANTHER; PTHR11003; POTASSIUM CHANNEL, SUBFAMILY K; 1.
DR   Pfam; PF07885; Ion_trans_2; 2.
DR   PRINTS; PR01333; 2POREKCHANEL.
DR   PRINTS; PR01095; TASKCHANNEL.
DR   SUPFAM; SSF81324; Voltage-gated potassium channels; 2.
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..394
FT                   /note="Potassium channel subfamily K member 18"
FT                   /id="PRO_0000312501"
FT   TOPO_DOM        1..31
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        32..52
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   INTRAMEM        114..140
FT                   /note="Pore-forming; Name=Pore-forming 1"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        142..162
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        163..292
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        293..313
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   INTRAMEM        326..340
FT                   /note="Pore-forming; Name=Pore-forming 2"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        347..367
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        368..394
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          210..215
FT                   /note="Interaction with calcineurin"
FT   REGION          261..266
FT                   /note="Interaction with YWHAH"
FT                   /evidence="ECO:0000269|PubMed:18397886"
FT   MOD_RES         264
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:18397886"
FT   MOD_RES         276
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000305|PubMed:14981085"
FT   CARBOHYD        83
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:20006580"
FT   MUTAGEN         83
FT                   /note="N->Q: Strongly reduced current amplitude and
FT                   localization to cell membrane."
FT                   /evidence="ECO:0000269|PubMed:20006580"
FT   MUTAGEN         132
FT                   /note="H->N: Insensitive to extracellular protons."
FT                   /evidence="ECO:0000269|PubMed:17962323"
FT   MUTAGEN         212
FT                   /note="I->A: Loss of interaction with calcineurin and
FT                   activation by elevated intracellular calcium; when
FT                   associated with A-214."
FT   MUTAGEN         214
FT                   /note="I->A: Strongly reduced activation by elevated
FT                   intracellular calcium. Loss of interaction with calcineurin
FT                   and activation by elevated intracellular calcium; when
FT                   associated with A-212."
FT   MUTAGEN         264
FT                   /note="S->A: Loss of interaction with YWHAH."
FT                   /evidence="ECO:0000269|PubMed:18397886"
FT   MUTAGEN         276
FT                   /note="S->A: Enhances basal channel activity and abolishes
FT                   stimulation by calcineurin."
FT                   /evidence="ECO:0000269|PubMed:14981085"
FT   CONFLICT        228
FT                   /note="K -> R (in Ref. 4; AAI15706/AAI04133)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        251
FT                   /note="K -> E (in Ref. 4; AAI15706/AAI04133)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   394 AA;  44403 MW;  82D03F7D7F0D5591 CRC64;
     MEAEEPPEAR RCCPEALGKA RGCCPEALGK LLPGLCFLCC LVTYALVGAA LFSAVEGRPD
     PEAEENPELK KFLDDLCNIL KCNLTVVEGS RKNLCEHLQH LKPQWLKAPQ DWSFLSALFF
     CCTVFSTVGY GHMYPVTRLG KFLCMLYALF GIPLMFLVLT DIGDILATIL SRAYSRFQAL
     LCLPHDIFKW RSLPLCRKQP DSKPVEEAIP QIVIDAGVDE LLNPQPSKDP PSPSCNVELF
     ERLVAREKKN KLQPPTRPVE RSNSCPELVL GRLSCSILSN LDEVGQQVER LDIPLPVIAL
     VVFAYISCAA AILPFWETEL GFEDAFYFCF VTLTTIGFGD IVLVHPHFFL FFSIYIIVGM
     EILFIAFKLM QNRLLHTYKT LMLFVCQREV SLPW
//