KCNJ8_HUMAN
ID KCNJ8_HUMAN Reviewed; 424 AA.
AC Q15842; O00657;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 199.
DE RecName: Full=ATP-sensitive inward rectifier potassium channel 8;
DE AltName: Full=Inward rectifier K(+) channel Kir6.1;
DE AltName: Full=Potassium channel, inwardly rectifying subfamily J member 8;
DE AltName: Full=uKATP-1;
GN Name=KCNJ8;
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 [GENOMIC DNA / MRNA].
RC TISSUE=Lung, and Placenta;
RX PubMed=8595887; DOI=10.1006/geno.1995.0018;
RA Inagaki N., Inazawa J., Seino S.;
RT "cDNA sequence, gene structure, and chromosomal localization of the human
RT ATP-sensitive potassium channel, uKATP-1, gene (KCNJ8).";
RL Genomics 30:102-104(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [3]
RP TISSUE SPECIFICITY.
RX PubMed=9573340; DOI=10.1016/s0378-1119(98)00086-9;
RA Erginel-Unaltuna N., Yang W.P., Blanar M.A.;
RT "Genomic organization and expression of KCNJ8/Kir6.1, a gene encoding a
RT subunit of an ATP-sensitive potassium channel.";
RL Gene 211:71-78(1998).
RN [4]
RP REVIEW ON J-WAVE SYNDROMES.
RX PubMed=20153265; DOI=10.1016/j.hrthm.2009.12.006;
RA Antzelevitch C., Yan G.X.;
RT "J wave syndromes.";
RL Heart Rhythm 7:549-558(2010).
RN [5]
RP POSSIBLE INVOLVEMENT IN SUSCEPTIBILITY TO J-WAVE SYNDROMES, VARIANT
RP LEU-422, AND CHARACTERIZATION OF VARIANT LEU-422.
RX PubMed=20558321; DOI=10.1016/j.hrthm.2010.06.016;
RA Medeiros-Domingo A., Tan B.H., Crotti L., Tester D.J., Eckhardt L.,
RA Cuoretti A., Kroboth S.L., Song C., Zhou Q., Kopp D., Schwartz P.J.,
RA Makielski J.C., Ackerman M.J.;
RT "Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP)
RT channel Kir6.1 as a pathogenic substrate for J-wave syndromes.";
RL Heart Rhythm 7:1466-1471(2010).
RN [6]
RP POSSIBLE INVOLVEMENT IN HTOCD, VARIANT HTOCD SER-176, AND CHARACTERIZATION
RP OF VARIANT HTOCD SER-176.
RX PubMed=24700710; DOI=10.1002/humu.22555;
RA Cooper P.E., Reutter H., Woelfle J., Engels H., Grange D.K.,
RA van Haaften G., van Bon B.W., Hoischen A., Nichols C.G.;
RT "Cantu syndrome resulting from activating mutation in the KCNJ8 gene.";
RL Hum. Mutat. 35:809-813(2014).
RN [7]
RP FUNCTION, CHARACTERIZATION OF VARIANT HTOCD MET-65, AND MUTAGENESIS OF
RP VAL-65.
RX PubMed=28842488; DOI=10.1074/jbc.m117.804971;
RA Cooper P.E., McClenaghan C., Chen X., Stary-Weinzinger A., Nichols C.G.;
RT "Conserved functional consequences of disease-associated mutations in the
RT slide-helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium
RT channel.";
RL J. Biol. Chem. 292:17387-17398(2017).
RN [8]
RP VARIANTS SIDS GLU-332 DEL AND ILE-346, AND CHARACTERIZATION OF VARIANTS
RP SIDS GLU-332 DEL AND ILE-346.
RX PubMed=21836131; DOI=10.1161/circgenetics.111.960195;
RA Tester D.J., Tan B.H., Medeiros-Domingo A., Song C., Makielski J.C.,
RA Ackerman M.J.;
RT "Loss-of-function mutations in the KCNJ8-encoded Kir6.1 KATP channel and
RT sudden infant death syndrome.";
RL Circ. Cardiovasc. Genet. 4:510-515(2011).
RN [9]
RP VARIANT HTOCD MET-65.
RX PubMed=24176758; DOI=10.1016/j.ejmg.2013.09.009;
RA Brownstein C.A., Towne M.C., Luquette L.J., Harris D.J., Marinakis N.S.,
RA Meinecke P., Kutsche K., Campeau P.M., Yu T.W., Margulies D.M.,
RA Agrawal P.B., Beggs A.H.;
RT "Mutation of KCNJ8 in a patient with Cantu syndrome with unique vascular
RT abnormalities - support for the role of K(ATP) channels in this
RT condition.";
RL Eur. J. Med. Genet. 56:678-682(2013).
CC -!- FUNCTION: This potassium channel is controlled by G proteins. Inward
CC rectifier potassium channels are characterized by a greater tendency to
CC allow potassium to flow into the cell rather than out of it. Their
CC voltage dependence is regulated by the concentration of extracellular
CC potassium; as external potassium is raised, the voltage range of the
CC channel opening shifts to more positive voltages. The inward
CC rectification is mainly due to the blockage of outward current by
CC internal magnesium. Can be blocked by external barium (By similarity).
CC {ECO:0000250|UniProtKB:Q63664, ECO:0000269|PubMed:28842488}.
CC -!- INTERACTION:
CC Q15842; P50402: EMD; NbExp=3; IntAct=EBI-17440235, EBI-489887;
CC Q15842; Q9NV12: TMEM140; NbExp=3; IntAct=EBI-17440235, EBI-2844246;
CC Q15842; Q969K7: TMEM54; NbExp=3; IntAct=EBI-17440235, EBI-3922833;
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein
CC {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Predominantly detected in fetal and adult heart.
CC {ECO:0000269|PubMed:9573340}.
CC -!- DISEASE: Note=Defects in KCNJ8 may be associated with susceptibility to
CC J-wave syndromes, a group of heart disorders characterized by early
CC repolarization events as indicated by abnormal J-wave manifestation on
CC electrocardiogram (ECG). The J point denotes the junction of the QRS
CC complex and the ST segment on the ECG, marking the end of
CC depolarization and the beginning of repolarization. An abnormal J wave
CC is a deflection with a dome or hump morphology immediately following
CC the QRS complex of the surface ECG. Examples of J-wave disorders are
CC arrhythmias associated with an early repolarization pattern in the
CC inferior or mid to lateral precordial leads, Brugada syndrome, some
CC cases of idiopathic ventricular fibrillation (VF) with an early
CC repolarization pattern in the inferior, inferolateral or global leads,
CC as well as arrhythmias associated with hypothermia.
CC {ECO:0000269|PubMed:20558321}.
CC -!- DISEASE: Sudden infant death syndrome (SIDS) [MIM:272120]: SIDS is the
CC sudden death of an infant younger than 1 year that remains unexplained
CC after a thorough case investigation, including performance of a
CC complete autopsy, examination of the death scene, and review of
CC clinical history. Pathophysiologic mechanisms for SIDS may include
CC respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory
CC instability, and inborn errors of metabolism, but definitive pathogenic
CC mechanisms precipitating an infant sudden death remain elusive.
CC {ECO:0000269|PubMed:21836131}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- DISEASE: Hypertrichotic osteochondrodysplasia (HTOCD) [MIM:239850]: A
CC rare disorder characterized by congenital hypertrichosis, neonatal
CC macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The
CC hypertrichosis leads to thick scalp hair, which extends onto the
CC forehead, and a general increase in body hair. In addition,
CC macrocephaly and coarse facial features, including a broad nasal
CC bridge, epicanthal folds, a wide mouth, and full lips, can be
CC suggestive of a storage disorder. About half of affected individuals
CC are macrosomic and edematous at birth, whereas in childhood they
CC usually have a muscular appearance with little subcutaneous fat.
CC Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid
CC vertebral bodies, coxa valga, osteopenia, enlarged medullary canals,
CC and metaphyseal widening of long bones have been reported. Cardiac
CC manifestations such as patent ductus arteriosus, ventricular
CC hypertrophy, pulmonary hypertension, and pericardial effusions are
CC present in approximately 80% of cases. Motor development is usually
CC delayed due to hypotonia. Most patients have a mild speech delay, and a
CC small percentage have learning difficulties or intellectual disability.
CC {ECO:0000269|PubMed:24176758, ECO:0000269|PubMed:24700710,
CC ECO:0000269|PubMed:28842488}. Note=The disease may be caused by
CC variants affecting distinct genetic loci, including the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the inward rectifier-type potassium channel (TC
CC 1.A.2.1) family. KCNJ8 subfamily. {ECO:0000305}.
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DR EMBL; D50312; BAA08851.1; -; mRNA.
DR EMBL; D50315; BAA08852.1; -; Genomic_DNA.
DR EMBL; BC000544; AAH00544.1; -; mRNA.
DR CCDS; CCDS8692.1; -.
DR RefSeq; NP_004973.1; NM_004982.3.
DR RefSeq; XP_005253415.1; XM_005253358.4.
DR RefSeq; XP_016874772.1; XM_017019283.1.
DR RefSeq; XP_016874773.1; XM_017019284.1.
DR AlphaFoldDB; Q15842; -.
DR SMR; Q15842; -.
DR BioGRID; 109966; 42.
DR ELM; Q15842; -.
DR IntAct; Q15842; 16.
DR STRING; 9606.ENSP00000240662; -.
DR ChEMBL; CHEMBL4770; -.
DR DrugBank; DB11148; Butamben.
DR DrugBank; DB01251; Gliquidone.
DR DrugBank; DB01289; Glisoxepide.
DR DrugBank; DB01016; Glyburide.
DR DrugBank; DB00922; Levosimendan.
DR DrugBank; DB00914; Phenformin.
DR DrugBank; DB01154; Thiamylal.
DR DrugBank; DB01392; Yohimbine.
DR DrugCentral; Q15842; -.
DR TCDB; 1.A.2.1.13; the inward rectifier k(+) channel (irk-c) family.
DR iPTMnet; Q15842; -.
DR PhosphoSitePlus; Q15842; -.
DR BioMuta; KCNJ8; -.
DR DMDM; 2493600; -.
DR jPOST; Q15842; -.
DR MassIVE; Q15842; -.
DR PaxDb; Q15842; -.
DR PeptideAtlas; Q15842; -.
DR PRIDE; Q15842; -.
DR ProteomicsDB; 60787; -.
DR Antibodypedia; 4014; 254 antibodies from 31 providers.
DR DNASU; 3764; -.
DR Ensembl; ENST00000240662.3; ENSP00000240662.2; ENSG00000121361.5.
DR Ensembl; ENST00000665145.1; ENSP00000499300.1; ENSG00000121361.5.
DR Ensembl; ENST00000667884.1; ENSP00000499462.1; ENSG00000121361.5.
DR GeneID; 3764; -.
DR KEGG; hsa:3764; -.
DR MANE-Select; ENST00000240662.3; ENSP00000240662.2; NM_004982.4; NP_004973.1.
DR UCSC; uc001rff.4; human.
DR CTD; 3764; -.
DR DisGeNET; 3764; -.
DR GeneCards; KCNJ8; -.
DR GeneReviews; KCNJ8; -.
DR HGNC; HGNC:6269; KCNJ8.
DR HPA; ENSG00000121361; Tissue enhanced (heart).
DR MalaCards; KCNJ8; -.
DR MIM; 239850; phenotype.
DR MIM; 272120; phenotype.
DR MIM; 600935; gene.
DR neXtProt; NX_Q15842; -.
DR OpenTargets; ENSG00000121361; -.
DR Orphanet; 130; Brugada syndrome.
DR Orphanet; 1517; Cantu syndrome.
DR PharmGKB; PA30050; -.
DR VEuPathDB; HostDB:ENSG00000121361; -.
DR eggNOG; KOG3827; Eukaryota.
DR GeneTree; ENSGT00990000203615; -.
DR HOGENOM; CLU_022738_4_0_1; -.
DR InParanoid; Q15842; -.
DR OMA; NSMRKGG; -.
DR OrthoDB; 956263at2759; -.
DR PhylomeDB; Q15842; -.
DR TreeFam; TF313676; -.
DR PathwayCommons; Q15842; -.
DR Reactome; R-HSA-1296025; ATP sensitive Potassium channels.
DR SignaLink; Q15842; -.
DR SIGNOR; Q15842; -.
DR BioGRID-ORCS; 3764; 7 hits in 1075 CRISPR screens.
DR GeneWiki; KCNJ8; -.
DR GenomeRNAi; 3764; -.
DR Pharos; Q15842; Tbio.
DR PRO; PR:Q15842; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q15842; protein.
DR Bgee; ENSG00000121361; Expressed in heart right ventricle and 156 other tissues.
DR ExpressionAtlas; Q15842; baseline and differential.
DR Genevisible; Q15842; HS.
DR GO; GO:0008282; C:inward rectifying potassium channel; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0030016; C:myofibril; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0031004; C:potassium ion-transporting ATPase complex; ISS:ARUK-UCL.
DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; ISS:ARUK-UCL.
DR GO; GO:0015272; F:ATP-activated inward rectifier potassium channel activity; IDA:BHF-UCL.
DR GO; GO:0019829; F:ATPase-coupled cation transmembrane transporter activity; ISS:ARUK-UCL.
DR GO; GO:0005242; F:inward rectifier potassium channel activity; IBA:GO_Central.
DR GO; GO:0017098; F:sulfonylurea receptor binding; IEA:Ensembl.
DR GO; GO:1902282; F:voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization; IMP:BHF-UCL.
DR GO; GO:0051607; P:defense response to virus; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0098662; P:inorganic cation transmembrane transport; ISS:ARUK-UCL.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0098915; P:membrane repolarization during ventricular cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; IDA:BHF-UCL.
DR GO; GO:0071805; P:potassium ion transmembrane transport; NAS:ARUK-UCL.
DR GO; GO:0006813; P:potassium ion transport; TAS:ProtInc.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL.
DR Gene3D; 2.60.40.1400; -; 1.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR041647; IRK_C.
DR InterPro; IPR016449; K_chnl_inward-rec_Kir.
DR InterPro; IPR003278; K_chnl_inward-rec_Kir6.1.
DR InterPro; IPR013518; K_chnl_inward-rec_Kir_cyto.
DR InterPro; IPR040445; Kir_TM.
DR PANTHER; PTHR11767; PTHR11767; 1.
DR PANTHER; PTHR11767:SF11; PTHR11767:SF11; 1.
DR Pfam; PF01007; IRK; 1.
DR Pfam; PF17655; IRK_C; 1.
DR PIRSF; PIRSF005465; GIRK_kir; 1.
DR PRINTS; PR01331; KIR61CHANNEL.
DR PRINTS; PR01320; KIRCHANNEL.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW Disease variant; Ion channel; Ion transport; Membrane; Phosphoprotein;
KW Potassium; Potassium transport; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1..424
FT /note="ATP-sensitive inward rectifier potassium channel 8"
FT /id="PRO_0000154947"
FT TOPO_DOM 1..69
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 70..94
FT /note="Helical; Name=M1"
FT /evidence="ECO:0000250"
FT TOPO_DOM 95..126
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT INTRAMEM 127..138
FT /note="Helical; Pore-forming; Name=H5"
FT /evidence="ECO:0000250"
FT INTRAMEM 139..145
FT /note="Pore-forming"
FT /evidence="ECO:0000250"
FT TOPO_DOM 146..154
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 155..176
FT /note="Helical; Name=M2"
FT /evidence="ECO:0000250"
FT TOPO_DOM 177..424
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT REGION 375..424
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 140..145
FT /note="Selectivity filter"
FT /evidence="ECO:0000250"
FT COMPBIAS 390..424
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 170
FT /note="Role in the control of polyamine-mediated channel
FT gating and in the blocking by intracellular magnesium"
FT /evidence="ECO:0000250"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97794"
FT VARIANT 65
FT /note="V -> M (in HTOCD; unknown pathological significance;
FT displays gain of function; increased open state stability,
FT reduced sensitivity to ATP inhibition and increased channel
FT activity; almost completely abolishes high affinity
FT sensitivity to glibenclamide, an inhibitor of ATP-sensitive
FT potassium channels; dbSNP:rs606231263)"
FT /evidence="ECO:0000269|PubMed:24176758,
FT ECO:0000269|PubMed:28842488"
FT /id="VAR_079518"
FT VARIANT 176
FT /note="C -> S (in HTOCD; unknown pathological significance;
FT displays gain of function; displays reduced ATP
FT sensitivity; dbSNP:rs606231264)"
FT /evidence="ECO:0000269|PubMed:24700710"
FT /id="VAR_075226"
FT VARIANT 332
FT /note="Missing (in SIDS; the mutant channel displays
FT reduced potassium currents compared to wild type)"
FT /evidence="ECO:0000269|PubMed:21836131"
FT /id="VAR_065878"
FT VARIANT 334
FT /note="V -> A (in dbSNP:rs34811413)"
FT /id="VAR_049670"
FT VARIANT 346
FT /note="V -> I (in SIDS; the mutant channel displays reduced
FT potassium currents compared to wild type;
FT dbSNP:rs147316959)"
FT /evidence="ECO:0000269|PubMed:21836131"
FT /id="VAR_065879"
FT VARIANT 422
FT /note="S -> L (found in Brugada syndrome and other J-wave
FT syndromes; unknown pathological significance; the mutant
FT channel displays an increase in glibenclamide-sensitive
FT potassium currents compared to wild type;
FT dbSNP:rs72554071)"
FT /evidence="ECO:0000269|PubMed:20558321"
FT /id="VAR_065225"
FT MUTAGEN 65
FT /note="V->L: No effect on channel activity."
FT /evidence="ECO:0000269|PubMed:28842488"
SQ SEQUENCE 424 AA; 47968 MW; 973EAA5900C6447C CRC64;
MLARKSIIPE EYVLARIAAE NLRKPRIRDR LPKARFIAKS GACNLAHKNI REQGRFLQDI
FTTLVDLKWR HTLVIFTMSF LCSWLLFAIM WWLVAFAHGD IYAYMEKSGM EKSGLESTVC
VTNVRSFTSA FLFSIEVQVT IGFGGRMMTE ECPLAITVLI LQNIVGLIIN AVMLGCIFMK
TAQAHRRAET LIFSRHAVIA VRNGKLCFMF RVGDLRKSMI ISASVRIQVV KKTTTPEGEV
VPIHQLDIPV DNPIESNNIF LVAPLIICHV IDKRSPLYDI SATDLANQDL EVIVILEGVV
ETTGITTQAR TSYIAEEIQW GHRFVSIVTE EEGVYSVDYS KFGNTVKVAA PRCSARELDE
KPSILIQTLQ KSELSHQNSL RKRNSMRRNN SMRRNNSIRR NNSSLMVPKV QFMTPEGNQN
TSES
