KCNK3_HUMAN
ID KCNK3_HUMAN Reviewed; 394 AA.
AC O14649; Q53SU2;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Potassium channel subfamily K member 3;
DE AltName: Full=Acid-sensitive potassium channel protein TASK-1;
DE AltName: Full=TWIK-related acid-sensitive K(+) channel 1;
DE AltName: Full=Two pore potassium channel KT3.1;
DE Short=Two pore K(+) channel KT3.1;
GN Name=KCNK3; Synonyms=TASK, TASK1;
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], AND FUNCTION.
RC TISSUE=Kidney;
RX PubMed=9312005; DOI=10.1093/emboj/16.17.5464;
RA Duprat F., Lesage F., Fink M., Reyes R., Heurteaux C., Lazdunski M.;
RT "TASK, a human background K+ channel to sense external pH variations near
RT physiological pH.";
RL EMBO J. 16:5464-5471(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Heart;
RX PubMed=10748056; DOI=10.1074/jbc.m001948200;
RA Lopes C.M.B., Gallagher P.G., Buck M.E., Butler M.H., Goldstein S.A.N.;
RT "Proton block and voltage gating are potassium-dependent in the cardiac
RT leak channel Kcnk3.";
RL J. Biol. Chem. 275:16969-16978(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP ACTIVATION.
RX PubMed=10321245; DOI=10.1038/8084;
RA Patel A.J., Honore E., Lesage F., Fink M., Romey G., Lazdunski M.;
RT "Inhalational anesthetics activate two-pore-domain background K+
RT channels.";
RL Nat. Neurosci. 2:422-426(1999).
RN [6]
RP MUTAGENESIS OF HIS-98.
RX PubMed=11680614; DOI=10.1007/s004240100620;
RA Ashmole I., Goodwin P.A., Stanfield P.R.;
RT "TASK-5, a novel member of the tandem pore K+ channel family.";
RL Pflugers Arch. 442:828-833(2001).
RN [7]
RP INTERACTION WITH KCNK1, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23169818; DOI=10.1126/scisignal.2003431;
RA Plant L.D., Zuniga L., Araki D., Marks J.D., Goldstein S.A.;
RT "SUMOylation silences heterodimeric TASK potassium channels containing K2P1
RT subunits in cerebellar granule neurons.";
RL Sci. Signal. 5:RA84-RA84(2012).
RN [8]
RP VARIANTS PPH4 LYS-8; ARG-97; LYS-182; CYS-192; ASP-203 AND LEU-221, AND
RP CHARACTERIZATION OF VARIANTS PPH4 LYS-8; ARG-97; LYS-182; CYS-192; ASP-203
RP AND LEU-221.
RX PubMed=23883380; DOI=10.1056/nejmoa1211097;
RA Ma L., Roman-Campos D., Austin E.D., Eyries M., Sampson K.S., Soubrier F.,
RA Germain M., Tregouet D.A., Borczuk A., Rosenzweig E.B., Girerd B.,
RA Montani D., Humbert M., Loyd J.E., Kass R.S., Chung W.K.;
RT "A novel channelopathy in pulmonary arterial hypertension.";
RL N. Engl. J. Med. 369:351-361(2013).
CC -!- FUNCTION: pH-dependent, voltage-insensitive, background potassium
CC channel protein. Rectification direction results from potassium ion
CC concentration on either side of the membrane. Acts as an outward
CC rectifier when external potassium concentration is low. When external
CC potassium concentration is high, current is inward.
CC {ECO:0000269|PubMed:23169818, ECO:0000269|PubMed:9312005}.
CC -!- SUBUNIT: Homodimer (Probable). Heterodimer with KCNK1.
CC {ECO:0000269|PubMed:23169818, ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23169818};
CC Multi-pass membrane protein {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Widespread expression in adult. Strongest
CC expression in pancreas and placenta. Lower expression in brain, lung,
CC prostate, heart, kidney, uterus, small intestine and colon.
CC -!- DISEASE: Pulmonary hypertension, primary, 4 (PPH4) [MIM:615344]: A rare
CC disorder characterized by plexiform lesions of proliferating
CC endothelial cells in pulmonary arterioles. The lesions lead to elevated
CC pulmonary arterial pression, right ventricular failure, and death. The
CC disease can occur from infancy throughout life and it has a mean age at
CC onset of 36 years. Penetrance is reduced. Although familial pulmonary
CC hypertension is rare, cases secondary to known etiologies are more
CC common and include those associated with the appetite-suppressant
CC drugs. {ECO:0000269|PubMed:23883380}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Inhibited by external acidification. Activated by
CC halothane and isoflurane.
CC -!- SIMILARITY: Belongs to the two pore domain potassium channel (TC
CC 1.A.1.8) family. {ECO:0000305}.
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DR EMBL; AF006823; AAC51777.1; -; mRNA.
DR EMBL; AF065163; AAG29340.1; -; mRNA.
DR EMBL; AC015977; AAY24312.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00678.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00679.1; -; Genomic_DNA.
DR CCDS; CCDS1727.1; -.
DR RefSeq; NP_002237.1; NM_002246.2.
DR PDB; 6RV2; X-ray; 3.00 A; A/B/C/D=1-259.
DR PDB; 6RV3; X-ray; 2.90 A; A/B/C/D=1-259.
DR PDB; 6RV4; X-ray; 3.10 A; A/B/C/D=1-259.
DR PDBsum; 6RV2; -.
DR PDBsum; 6RV3; -.
DR PDBsum; 6RV4; -.
DR AlphaFoldDB; O14649; -.
DR SMR; O14649; -.
DR BioGRID; 109978; 5.
DR IntAct; O14649; 2.
DR MINT; O14649; -.
DR STRING; 9606.ENSP00000306275; -.
DR BindingDB; O14649; -.
DR ChEMBL; CHEMBL2321613; -.
DR DrugBank; DB00561; Doxapram.
DR DrugBank; DB01159; Halothane.
DR DrugCentral; O14649; -.
DR GuidetoPHARMACOLOGY; 515; -.
DR TCDB; 1.A.1.9.2; the voltage-gated ion channel (vic) superfamily.
DR GlyGen; O14649; 1 site.
DR iPTMnet; O14649; -.
DR PhosphoSitePlus; O14649; -.
DR BioMuta; KCNK3; -.
DR MassIVE; O14649; -.
DR PaxDb; O14649; -.
DR PeptideAtlas; O14649; -.
DR PRIDE; O14649; -.
DR ProteomicsDB; 48147; -.
DR Antibodypedia; 13387; 238 antibodies from 28 providers.
DR DNASU; 3777; -.
DR Ensembl; ENST00000302909.4; ENSP00000306275.3; ENSG00000171303.8.
DR GeneID; 3777; -.
DR KEGG; hsa:3777; -.
DR MANE-Select; ENST00000302909.4; ENSP00000306275.3; NM_002246.3; NP_002237.1.
DR UCSC; uc002rhn.3; human.
DR CTD; 3777; -.
DR DisGeNET; 3777; -.
DR GeneCards; KCNK3; -.
DR GeneReviews; KCNK3; -.
DR HGNC; HGNC:6278; KCNK3.
DR HPA; ENSG00000171303; Tissue enriched (adrenal).
DR MalaCards; KCNK3; -.
DR MIM; 603220; gene.
DR MIM; 615344; phenotype.
DR neXtProt; NX_O14649; -.
DR OpenTargets; ENSG00000171303; -.
DR Orphanet; 275777; Heritable pulmonary arterial hypertension.
DR PharmGKB; PA30060; -.
DR VEuPathDB; HostDB:ENSG00000171303; -.
DR eggNOG; KOG4404; Eukaryota.
DR GeneTree; ENSGT00940000158248; -.
DR HOGENOM; CLU_022504_4_0_1; -.
DR InParanoid; O14649; -.
DR OMA; TCMEQSH; -.
DR OrthoDB; 1109218at2759; -.
DR PhylomeDB; O14649; -.
DR TreeFam; TF313947; -.
DR PathwayCommons; O14649; -.
DR Reactome; R-HSA-1299316; TWIK-releated acid-sensitive K+ channel (TASK).
DR Reactome; R-HSA-5576886; Phase 4 - resting membrane potential.
DR SignaLink; O14649; -.
DR SIGNOR; O14649; -.
DR BioGRID-ORCS; 3777; 7 hits in 1067 CRISPR screens.
DR ChiTaRS; KCNK3; human.
DR GeneWiki; KCNK3; -.
DR GenomeRNAi; 3777; -.
DR Pharos; O14649; Tclin.
DR PRO; PR:O14649; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; O14649; protein.
DR Bgee; ENSG00000171303; Expressed in left adrenal gland and 144 other tissues.
DR ExpressionAtlas; O14649; baseline and differential.
DR Genevisible; O14649; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IMP:UniProtKB.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0005216; F:ion channel activity; IMP:UniProtKB.
DR GO; GO:0005252; F:open rectifier potassium channel activity; IEA:Ensembl.
DR GO; GO:0015271; F:outward rectifier potassium channel activity; IBA:GO_Central.
DR GO; GO:0005267; F:potassium channel activity; TAS:ProtInc.
DR GO; GO:0022841; F:potassium ion leak channel activity; IDA:UniProtKB.
DR GO; GO:0008022; F:protein C-terminus binding; IEA:Ensembl.
DR GO; GO:0044548; F:S100 protein binding; IPI:UniProtKB.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0071294; P:cellular response to zinc ion; IEA:Ensembl.
DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc.
DR GO; GO:0090102; P:cochlea development; IEA:Ensembl.
DR GO; GO:0034220; P:ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; IEA:Ensembl.
DR GO; GO:1903818; P:positive regulation of voltage-gated potassium channel activity; IEA:Ensembl.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0006813; P:potassium ion transport; TAS:ProtInc.
DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0030322; P:stabilization of membrane potential; IBA:GO_Central.
DR InterPro; IPR003280; 2pore_dom_K_chnl.
DR InterPro; IPR003092; 2pore_dom_K_chnl_TASK.
DR InterPro; IPR013099; K_chnl_dom.
DR InterPro; IPR005406; KCNK3.
DR PANTHER; PTHR11003; PTHR11003; 1.
DR PANTHER; PTHR11003:SF138; PTHR11003:SF138; 1.
DR Pfam; PF07885; Ion_trans_2; 2.
DR PIRSF; PIRSF038061; K_channel_subfamily_K_type; 1.
DR PRINTS; PR01333; 2POREKCHANEL.
DR PRINTS; PR01584; TASK1CHANNEL.
DR PRINTS; PR01095; TASKCHANNEL.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Disease variant; Glycoprotein; Ion channel;
KW Ion transport; Membrane; Potassium; Potassium channel; Potassium transport;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..394
FT /note="Potassium channel subfamily K member 3"
FT /id="PRO_0000101744"
FT TOPO_DOM 1..8
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 9..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT INTRAMEM 78..101
FT /note="Pore-forming; Name=Pore-forming 1"
FT /evidence="ECO:0000255"
FT TRANSMEM 108..128
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 129..158
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 159..179
FT /note="Helical"
FT /evidence="ECO:0000255"
FT INTRAMEM 184..207
FT /note="Pore-forming; Name=Pore-forming 2"
FT /evidence="ECO:0000255"
FT TRANSMEM 223..243
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 244..394
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 266..286
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 338..357
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 338..352
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 53
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 8
FT /note="T -> K (in PPH4; loss of function; channel activity
FT can be rescued with the use of the phospholipase A2
FT inhibitor ONO-RS-082; dbSNP:rs1085307438)"
FT /evidence="ECO:0000269|PubMed:23883380"
FT /id="VAR_070126"
FT VARIANT 97
FT /note="G -> R (in PPH4; loss of function;
FT dbSNP:rs398123040)"
FT /evidence="ECO:0000269|PubMed:23883380"
FT /id="VAR_070127"
FT VARIANT 182
FT /note="E -> K (in PPH4; loss of function; channel activity
FT can be rescued with the use of the phospholipase A2
FT inhibitor ONO-RS-082; dbSNP:rs398123042)"
FT /evidence="ECO:0000269|PubMed:23883380"
FT /id="VAR_070128"
FT VARIANT 192
FT /note="Y -> C (in PPH4; loss of function;
FT dbSNP:rs398123043)"
FT /evidence="ECO:0000269|PubMed:23883380"
FT /id="VAR_070129"
FT VARIANT 203
FT /note="G -> D (in PPH4; loss of function; channel activity
FT cannot be rescued with the use of the phospholipase A2
FT inhibitor ONO-RS-082; dbSNP:rs398123039)"
FT /evidence="ECO:0000269|PubMed:23883380"
FT /id="VAR_070130"
FT VARIANT 221
FT /note="V -> L (in PPH4; loss of function;
FT dbSNP:rs398123041)"
FT /evidence="ECO:0000269|PubMed:23883380"
FT /id="VAR_070131"
FT MUTAGEN 98
FT /note="H->N: Greatly reduces pH sensitivity."
FT /evidence="ECO:0000269|PubMed:11680614"
FT HELIX 3..51
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 56..73
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 80..91
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 104..147
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 156..181
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 186..197
FT /evidence="ECO:0007829|PDB:6RV3"
FT STRAND 203..205
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 210..212
FT /evidence="ECO:0007829|PDB:6RV2"
FT HELIX 213..216
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 218..241
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 244..247
FT /evidence="ECO:0007829|PDB:6RV3"
FT HELIX 249..259
FT /evidence="ECO:0007829|PDB:6RV3"
SQ SEQUENCE 394 AA; 43518 MW; 9FF4C8266F615FB7 CRC64;
MKRQNVRTLA LIVCTFTYLL VGAAVFDALE SEPELIERQR LELRQQELRA RYNLSQGGYE
ELERVVLRLK PHKAGVQWRF AGSFYFAITV ITTIGYGHAA PSTDGGKVFC MFYALLGIPL
TLVMFQSLGE RINTLVRYLL HRAKKGLGMR RADVSMANMV LIGFFSCIST LCIGAAAFSH
YEHWTFFQAY YYCFITLTTI GFGDYVALQK DQALQTQPQY VAFSFVYILT GLTVIGAFLN
LVVLRFMTMN AEDEKRDAEH RALLTRNGQA GGGGGGGSAH TTDTASSTAA AGGGGFRNVY
AEVLHFQSMC SCLWYKSREK LQYSIPMIIP RDLSTSDTCV EQSHSSPGGG GRYSDTPSRR
CLCSGAPRSA ISSVSTGLHS LSTFRGLMKR RSSV
