ID KCNJ6_HUMAN Reviewed; 423 AA. AC P48051; Q3MJ74; Q53WW6; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1996, sequence version 1. DT 24-JAN-2024, entry version 192. DE RecName: Full=G protein-activated inward rectifier potassium channel 2; DE Short=GIRK-2; DE AltName: Full=BIR1; DE AltName: Full=Inward rectifier K(+) channel Kir3.2; DE AltName: Full=KATP-2; DE AltName: Full=Potassium channel, inwardly rectifying subfamily J member 6; GN Name=KCNJ6; Synonyms=GIRK2, KATP2, KCNJ7; 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]. RC TISSUE=Insulinoma; RX PubMed=7592809; DOI=10.1074/jbc.270.44.26086; RA Ferrer J., Nichols C.G., Makhina E.N., Salkoff L., Bernstein J., RA Gerhard D., Wasson J., Ramanadham S., Permutt A.; RT "Pancreatic islet cells express a family of inwardly rectifying K+ channel RT subunits which interact to form G-protein-activated channels."; RL J. Biol. Chem. 270:26086-26091(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Hippocampus; RA Dissmann E., Karschin A.; RT "Subunit interactions in the assembly of neuronal G protein-activated RT inwardly rectifying K+ channels."; RL Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Brain; RA Ohira M., Seki N., Nagase T., Suzuki E., Nomura N., Ohara O., Saito T., RA Ichikawa H., Ohki M.; RT "Gene identification in the 1.6 Mb of the Down syndrome region on RT chromosome 21."; RL Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Cerebellum; RX PubMed=10659995; DOI=10.1016/s0898-6568(99)00059-5; RA Schoots O., Wilson J.M., Ethier N., Bigras E., Hebert T.E., Van Tol H.H.M.; RT "Co-expression of human Kir3 subunits can yield channels with different RT functional properties."; RL Cell. Signal. 11:871-883(1999). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; 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 [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 17-423. RX PubMed=7796919; DOI=10.1016/0014-5793(95)00498-x; RA Sakura H., Bond C., Warren-Perry M., Horsley S., Kearney L., Tucker S., RA Adelman J., Turner R., Ashcroft F.M.; RT "Characterization and variation of a human inwardly-rectifying-K-channel RT gene (KCNJ6): a putative ATP-sensitive K-channel subunit."; RL FEBS Lett. 367:193-197(1995). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 116-211. RX PubMed=7729621; DOI=10.2337/diab.44.5.592; RA Tsaur M.-L., Menzel S., Lai F.-P., Espinosa R. III, Concannon P., RA Spielman R.S., Hanis C.L., Cox N.J., le Beau M.M., German M.S., Jan L.Y., RA Bell G.I., Stoffel M.; RT "Isolation of a cDNA clone encoding a KATP channel-like protein expressed RT in insulin-secreting cells, localization of the human gene to chromosome RT band 21q22.1, and linkage studies with NIDDM."; RL Diabetes 44:592-596(1995). RN [8] RP INVOLVEMENT IN KPLBS, AND VARIANTS KPLBS THR-152 DEL AND SER-154. RX PubMed=25620207; DOI=10.1016/j.ajhg.2014.12.011; RA Masotti A., Uva P., Davis-Keppen L., Basel-Vanagaite L., Cohen L., RA Pisaneschi E., Celluzzi A., Bencivenga P., Fang M., Tian M., Xu X., RA Cappa M., Dallapiccola B.; RT "Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying RT K+ channel encoded by KCNJ6."; RL Am. J. Hum. Genet. 96:295-300(2015). CC -!- FUNCTION: This potassium channel may be involved in the regulation of CC insulin secretion by glucose and/or neurotransmitters acting through G- CC protein-coupled receptors. Inward rectifier potassium channels are CC characterized by a greater tendency to allow potassium to flow into the CC cell rather than out of it. Their voltage dependence is regulated by CC the concentration of extracellular potassium; as external potassium is CC raised, the voltage range of the channel opening shifts to more CC positive voltages. The inward rectification is mainly due to the CC blockage of outward current by internal magnesium. CC -!- SUBUNIT: Associates with GIRK1 or GIRK4 to form a G-protein-activated CC heteromultimer pore-forming unit. The resulting inward current is much CC larger. Interacts (via PDZ-binding motif) with SNX27 (via PDZ domain); CC the interaction is required when endocytosed to prevent degradation in CC lysosomes and promote recycling to the plasma membrane (By similarity). CC {ECO:0000250}. CC -!- INTERACTION: CC P48051; Q9NVV5-2: AIG1; NbExp=3; IntAct=EBI-12017638, EBI-11957045; CC P48051; P05090: APOD; NbExp=3; IntAct=EBI-12017638, EBI-715495; CC P48051; Q92843: BCL2L2; NbExp=3; IntAct=EBI-12017638, EBI-707714; CC P48051; O15155: BET1; NbExp=3; IntAct=EBI-12017638, EBI-749204; CC P48051; Q96DZ9-2: CMTM5; NbExp=3; IntAct=EBI-12017638, EBI-11522780; CC P48051; Q9BT09: CNPY3; NbExp=3; IntAct=EBI-12017638, EBI-2835965; CC P48051; P29400-2: COL4A5; NbExp=3; IntAct=EBI-12017638, EBI-12211159; CC P48051; P56851: EDDM3B; NbExp=3; IntAct=EBI-12017638, EBI-10215665; CC P48051; Q9UKR5: ERG28; NbExp=3; IntAct=EBI-12017638, EBI-711490; CC P48051; O75063: FAM20B; NbExp=3; IntAct=EBI-12017638, EBI-11090967; CC P48051; Q9Y3D6: FIS1; NbExp=3; IntAct=EBI-12017638, EBI-3385283; CC P48051; Q9BWH2: FUNDC2; NbExp=3; IntAct=EBI-12017638, EBI-714482; CC P48051; Q9H0Q3: FXYD6; NbExp=3; IntAct=EBI-12017638, EBI-713304; CC P48051; A0A024R8L2: hCG_1987119; NbExp=3; IntAct=EBI-12017638, EBI-14103818; CC P48051; P30519: HMOX2; NbExp=3; IntAct=EBI-12017638, EBI-712096; CC P48051; O60725: ICMT; NbExp=3; IntAct=EBI-12017638, EBI-11721771; CC P48051; P11215: ITGAM; NbExp=3; IntAct=EBI-12017638, EBI-2568251; CC P48051; O95214: LEPROTL1; NbExp=3; IntAct=EBI-12017638, EBI-750776; CC P48051; Q9UBY5: LPAR3; NbExp=3; IntAct=EBI-12017638, EBI-12033434; CC P48051; Q7L5N7: LPCAT2; NbExp=3; IntAct=EBI-12017638, EBI-4280011; CC P48051; P30301: MIP; NbExp=3; IntAct=EBI-12017638, EBI-8449636; CC P48051; Q9NZG7: NINJ2; NbExp=3; IntAct=EBI-12017638, EBI-10317425; CC P48051; Q8N912: NRAC; NbExp=3; IntAct=EBI-12017638, EBI-12051377; CC P48051; Q53FV1: ORMDL2; NbExp=3; IntAct=EBI-12017638, EBI-11075081; CC P48051; Q96HA9: PEX11G; NbExp=3; IntAct=EBI-12017638, EBI-17284886; CC P48051; Q9Y5Y5: PEX16; NbExp=3; IntAct=EBI-12017638, EBI-981985; CC P48051; Q9Y342: PLLP; NbExp=3; IntAct=EBI-12017638, EBI-3919291; CC P48051; Q01453: PMP22; NbExp=3; IntAct=EBI-12017638, EBI-2845982; CC P48051; P54315: PNLIPRP1; NbExp=3; IntAct=EBI-12017638, EBI-8652812; CC P48051; Q9NS64: RPRM; NbExp=3; IntAct=EBI-12017638, EBI-1052363; CC P48051; Q5QGT7: RTP2; NbExp=3; IntAct=EBI-12017638, EBI-10244780; CC P48051; Q969E2: SCAMP4; NbExp=3; IntAct=EBI-12017638, EBI-4403649; CC P48051; Q14162: SCARF1; NbExp=3; IntAct=EBI-12017638, EBI-12056025; CC P48051; O00767: SCD; NbExp=3; IntAct=EBI-12017638, EBI-2684237; CC P48051; A2A2V5: SERTM1; NbExp=3; IntAct=EBI-12017638, EBI-17284533; CC P48051; P02808: STATH; NbExp=3; IntAct=EBI-12017638, EBI-738687; CC P48051; P0DN84: STRIT1; NbExp=3; IntAct=EBI-12017638, EBI-12200293; CC P48051; Q9BQG1: SYT3; NbExp=3; IntAct=EBI-12017638, EBI-17284568; CC P48051; Q9C0I4: THSD7B; NbExp=3; IntAct=EBI-12017638, EBI-311394; CC P48051; Q9BZW4: TM6SF2; NbExp=3; IntAct=EBI-12017638, EBI-13082040; CC P48051; Q6UX40: TMEM107; NbExp=3; IntAct=EBI-12017638, EBI-12845616; CC P48051; A0PK00: TMEM120B; NbExp=3; IntAct=EBI-12017638, EBI-10171534; CC P48051; Q969S6: TMEM203; NbExp=3; IntAct=EBI-12017638, EBI-12274070; CC P48051; Q9BTX3: TMEM208; NbExp=3; IntAct=EBI-12017638, EBI-12876824; CC P48051; A2RU14: TMEM218; NbExp=3; IntAct=EBI-12017638, EBI-10173151; CC P48051; Q6ZT21: TMPPE; NbExp=3; IntAct=EBI-12017638, EBI-11724433; CC P48051; O14798: TNFRSF10C; NbExp=3; IntAct=EBI-12017638, EBI-717441; CC P48051; Q5TGU0: TSPO2; NbExp=3; IntAct=EBI-12017638, EBI-12195249; CC P48051; Q9Y5Z9: UBIAD1; NbExp=3; IntAct=EBI-12017638, EBI-2819725; CC P48051; Q53HI1: UNC50; NbExp=3; IntAct=EBI-12017638, EBI-7601760; CC P48051; O75841: UPK1B; NbExp=3; IntAct=EBI-12017638, EBI-12237619; CC P48051; Q6UX27-3: VSTM1; NbExp=3; IntAct=EBI-12017638, EBI-12190699; CC P48051; Q9Y548: YIPF1; NbExp=3; IntAct=EBI-12017638, EBI-7850136; CC P48051; Q96EC8: YIPF6; NbExp=3; IntAct=EBI-12017638, EBI-751210; CC P48051; Q6UX98: ZDHHC24; NbExp=3; IntAct=EBI-12017638, EBI-10254561; CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein. CC -!- TISSUE SPECIFICITY: Most abundant in cerebellum, and to a lesser degree CC in islets and exocrine pancreas. CC -!- DISEASE: Keppen-Lubinsky syndrome (KPLBS) [MIM:614098]: A rare disease CC characterized by severe developmental delay, intellectual disability, CC severe generalized lipodystrophy, dysmorphic features including CC microcephaly, large prominent eyes, narrow nasal bridge, tented upper CC lip, high palate, open mouth, tightly adherent skin, and aged CC appearance. {ECO:0000269|PubMed:25620207}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the inward rectifier-type potassium channel CC (TC 1.A.2.1) family. KCNJ6 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U24660; AAC50258.1; -; mRNA. DR EMBL; L78480; AAB02277.1; -; mRNA. DR EMBL; D87327; BAA13331.1; -; mRNA. DR EMBL; U52153; AAB07044.1; -; mRNA. DR EMBL; BC101547; AAI01548.1; -; mRNA. DR EMBL; S78685; AAB34738.2; -; Genomic_DNA. DR EMBL; S78684; AAB34738.2; JOINED; Genomic_DNA. DR EMBL; G02354; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS42927.1; -. DR PIR; I38979; I38979. DR RefSeq; NP_002231.1; NM_002240.4. DR AlphaFoldDB; P48051; -. DR SMR; P48051; -. DR BioGRID; 109965; 74. DR IntAct; P48051; 71. DR MINT; P48051; -. DR STRING; 9606.ENSP00000477437; -. DR BindingDB; P48051; -. DR ChEMBL; CHEMBL2406895; -. DR DrugBank; DB00898; Ethanol. DR DrugBank; DB01159; Halothane. DR DrugBank; DB08954; Ifenprodil. DR DrugBank; DB11633; Isavuconazole. DR DrugCentral; P48051; -. DR GuidetoPHARMACOLOGY; 435; -. DR TCDB; 1.A.2.1.10; the inward rectifier k(+) channel (irk-c) family. DR iPTMnet; P48051; -. DR PhosphoSitePlus; P48051; -. DR BioMuta; KCNJ6; -. DR DMDM; 1352487; -. DR jPOST; P48051; -. DR MassIVE; P48051; -. DR PaxDb; 9606-ENSP00000477437; -. DR PeptideAtlas; P48051; -. DR ProteomicsDB; 55842; -. DR Antibodypedia; 23226; 306 antibodies from 35 providers. DR DNASU; 3763; -. DR Ensembl; ENST00000609713.2; ENSP00000477437.1; ENSG00000157542.11. DR Ensembl; ENST00000645093.1; ENSP00000493772.1; ENSG00000157542.11. DR GeneID; 3763; -. DR KEGG; hsa:3763; -. DR MANE-Select; ENST00000609713.2; ENSP00000477437.1; NM_002240.5; NP_002231.1. DR UCSC; uc002ywn.2; human. DR AGR; HGNC:6267; -. DR CTD; 3763; -. DR DisGeNET; 3763; -. DR GeneCards; KCNJ6; -. DR HGNC; HGNC:6267; KCNJ6. DR HPA; ENSG00000157542; Tissue enhanced (brain, pituitary gland). DR MalaCards; KCNJ6; -. DR MIM; 600877; gene. DR MIM; 614098; phenotype. DR neXtProt; NX_P48051; -. DR OpenTargets; ENSG00000157542; -. DR Orphanet; 435628; Keppen-Lubinsky syndrome. DR PharmGKB; PA30049; -. DR VEuPathDB; HostDB:ENSG00000157542; -. DR eggNOG; KOG3827; Eukaryota. DR GeneTree; ENSGT01080000257365; -. DR HOGENOM; CLU_022738_11_0_1; -. DR InParanoid; P48051; -. DR OMA; ETNTPPY; -. DR OrthoDB; 4126787at2759; -. DR PhylomeDB; P48051; -. DR TreeFam; TF313676; -. DR PathwayCommons; P48051; -. DR Reactome; R-HSA-1296041; Activation of G protein gated Potassium channels. DR Reactome; R-HSA-997272; Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits. DR SignaLink; P48051; -. DR BioGRID-ORCS; 3763; 13 hits in 1074 CRISPR screens. DR ChiTaRS; KCNJ6; human. DR GeneWiki; KCNJ6; -. DR GenomeRNAi; 3763; -. DR Pharos; P48051; Tchem. DR PRO; PR:P48051; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; P48051; Protein. DR Bgee; ENSG00000157542; Expressed in substantia nigra pars reticulata and 79 other cell types or tissues. DR GO; GO:0005794; C:Golgi apparatus; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; HDA:UniProtKB. DR GO; GO:0008076; C:voltage-gated potassium channel complex; TAS:ProtInc. DR GO; GO:0015467; F:G-protein activated inward rectifier potassium channel activity; TAS:ProtInc. DR GO; GO:0005242; F:inward rectifier potassium channel activity; IBA:GO_Central. DR GO; GO:1990573; P:potassium ion import across plasma membrane; IBA:GO_Central. DR GO; GO:0006813; P:potassium ion transport; TAS:ProtInc. DR GO; GO:0034765; P:regulation of monoatomic ion transmembrane transport; IBA:GO_Central. DR Gene3D; 1.10.287.70; -; 1. DR Gene3D; 2.60.40.1400; G protein-activated inward rectifier potassium channel 1; 1. DR InterPro; IPR014756; Ig_E-set. DR InterPro; IPR041647; IRK_C. DR InterPro; IPR016449; K_chnl_inward-rec_Kir. DR InterPro; IPR003275; K_chnl_inward-rec_Kir3.2. DR InterPro; IPR013518; K_chnl_inward-rec_Kir_cyto. DR InterPro; IPR040445; Kir_TM. DR PANTHER; PTHR11767:SF19; G PROTEIN-ACTIVATED INWARD RECTIFIER POTASSIUM CHANNEL 2; 1. DR PANTHER; PTHR11767; INWARD RECTIFIER POTASSIUM CHANNEL; 1. DR Pfam; PF01007; IRK; 1. DR Pfam; PF17655; IRK_C; 1. DR PIRSF; PIRSF005465; GIRK_kir; 1. DR PRINTS; PR01328; KIR32CHANNEL. DR PRINTS; PR01320; KIRCHANNEL. DR SUPFAM; SSF81296; E set domains; 1. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 1. DR Genevisible; P48051; HS. PE 1: Evidence at protein level; KW Congenital generalized lipodystrophy; Disease variant; KW Intellectual disability; Ion channel; Ion transport; Membrane; KW Phosphoprotein; Potassium; Potassium transport; Reference proteome; KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel. FT CHAIN 1..423 FT /note="G protein-activated inward rectifier potassium FT channel 2" FT /id="PRO_0000154942" FT TOPO_DOM 1..89 FT /note="Cytoplasmic" FT /evidence="ECO:0000250" FT TRANSMEM 90..114 FT /note="Helical; Name=M1" FT /evidence="ECO:0000250" FT TOPO_DOM 115..138 FT /note="Extracellular" FT /evidence="ECO:0000250" FT INTRAMEM 139..150 FT /note="Helical; Pore-forming; Name=H5" FT /evidence="ECO:0000250" FT INTRAMEM 151..157 FT /note="Pore-forming" FT /evidence="ECO:0000250" FT TOPO_DOM 158..166 FT /note="Extracellular" FT /evidence="ECO:0000250" FT TRANSMEM 167..188 FT /note="Helical; Name=M2" FT /evidence="ECO:0000250" FT TOPO_DOM 189..423 FT /note="Cytoplasmic" FT /evidence="ECO:0000250" FT REGION 390..423 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 152..157 FT /note="Selectivity filter" FT /evidence="ECO:0000250" FT MOTIF 420..423 FT /note="PDZ-binding" FT COMPBIAS 392..423 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 182 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 16 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P48542" FT MOD_RES 23 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P48542" FT VARIANT 152 FT /note="Missing (in KPLBS)" FT /evidence="ECO:0000269|PubMed:25620207" FT /id="VAR_073430" FT VARIANT 154 FT /note="G -> S (in KPLBS; dbSNP:rs786204795)" FT /evidence="ECO:0000269|PubMed:25620207" FT /id="VAR_073431" SQ SEQUENCE 423 AA; 48451 MW; 7A02F6B0FBF8B7D4 CRC64; MAKLTESMTN VLEGDSMDQD VESPVAIHQP KLPKQARDDL PRHISRDRTK RKIQRYVRKD GKCNVHHGNV RETYRYLTDI FTTLVDLKWR FNLLIFVMVY TVTWLFFGMI WWLIAYIRGD MDHIEDPSWT PCVTNLNGFV SAFLFSIETE TTIGYGYRVI TDKCPEGIIL LLIQSVLGSI VNAFMVGCMF VKISQPKKRA ETLVFSTHAV ISMRDGKLCL MFRVGDLRNS HIVEASIRAK LIKSKQTSEG EFIPLNQTDI NVGYYTGDDR LFLVSPLIIS HEINQQSPFW EISKAQLPKE ELEIVVILEG MVEATGMTCQ ARSSYITSEI LWGYRFTPVL TLEDGFYEVD YNSFHETYET STPSLSAKEL AELASRAELP LSWSVSSKLN QHAELETEEE EKNLEEQTER NGDVANLENE SKV //