ID   KCJ18_HUMAN             Reviewed;         433 AA.
AC   B7U540; A0A075B742; A0A142CKZ1; A0A142CKZ2;
DT   13-JUL-2010, integrated into UniProtKB/Swiss-Prot.
DT   14-OCT-2015, sequence version 3.
DT   05-FEB-2025, entry version 109.
DE   RecName: Full=Inward rectifier potassium channel 18;
DE   AltName: Full=Inward rectifier K(+) channel Kir2.6 {ECO:0000303|PubMed:20074522};
DE   AltName: Full=Potassium channel, inwardly rectifying subfamily J member 18;
GN   Name=KCNJ18;
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, TRANSPORTER ACTIVITY, INDUCTION BY
RP   TRIIODOTHYRONINE, TISSUE SPECIFICITY, PHOSPHORYLATION, VARIANTS TTPP2
RP   MET-140; HIS-205; MET-354 AND ARG-366, CHARACTERIZATION OF VARIANTS TTPP2
RP   HIS-205; MET-354 AND ARG-366, MUTAGENESIS OF THR-354, AND VARIANTS
RP   39-ARG-ARG-40 DELINS GLN-HIS AND VAL-249.
RC   TISSUE=Brain;
RX   PubMed=20074522; DOI=10.1016/j.cell.2009.12.024;
RA   Ryan D.P., da Silva M.R., Soong T.W., Fontaine B., Donaldson M.R.,
RA   Kung A.W., Jongjaroenprasert W., Liang M.C., Khoo D.H., Cheah J.S.,
RA   Ho S.C., Bernstein H.S., Maciel R.M., Brown R.H. Jr., Ptacek L.J.;
RT   "Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic
RT   hypokalemic periodic paralysis.";
RL   Cell 140:88-98(2010).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS 39-ARG-ARG-40 DELINS GLN-HIS;
RP   GLU-56 AND VAL-249, AND FUNCTION.
RX   PubMed=27008341; DOI=10.1007/s00438-016-1185-0;
RA   Paninka R.M., Mazzotti D.R., Kizys M.M., Vidi A.C., Rodrigues H.,
RA   Silva S.P., Kunii I.S., Furuzawa G.K., Arcisio-Miranda M.,
RA   Dias-da-Silva M.R.;
RT   "Whole genome and exome sequencing realignment supports the assignment of
RT   KCNJ12, KCNJ17, and KCNJ18 paralogous genes in thyrotoxic periodic
RT   paralysis locus: functional characterization of two polymorphic Kir2.6
RT   isoforms.";
RL   Mol. Genet. Genomics 291:1535-1544(2016).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16625196; DOI=10.1038/nature04689;
RA   Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA   Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA   Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA   Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA   DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA   Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA   Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA   LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA   Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA   Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA   Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA   Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA   Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT   "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT   human lineage.";
RL   Nature 440:1045-1049(2006).
RN   [4]
RP   SUBCELLULAR LOCATION, TRANSPORTER ACTIVITY, SUBUNIT, AND MUTAGENESIS OF
RP   LEU-156.
RX   PubMed=21209095; DOI=10.1074/jbc.m110.170597;
RA   Dassau L., Conti L.R., Radeke C.M., Ptacek L.J., Vandenberg C.A.;
RT   "Kir2.6 regulates the surface expression of Kir2.x inward rectifier
RT   potassium channels.";
RL   J. Biol. Chem. 286:9526-9541(2011).
RN   [5]
RP   VARIANT TTPP2 MET-168, CHARACTERIZATION OF VARIANT TTPP2 MET-168, VARIANTS
RP   CYS-43 AND PRO-200, CHARACTERIZATION OF VARIANTS CYS-43 AND PRO-200,
RP   TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=21665951; DOI=10.1074/jbc.m111.249656;
RA   Cheng C.J., Lin S.H., Lo Y.F., Yang S.S., Hsu Y.J., Cannon S.C.,
RA   Huang C.L.;
RT   "Identification and functional characterization of Kir2.6 mutations
RT   associated with non-familial hypokalemic periodic paralysis.";
RL   J. Biol. Chem. 286:27425-27435(2011).
RN   [6]
RP   VARIANTS TTPP2 126-GLN--HIS-344 DEL; THR-360 AND LYS-388.
RX   PubMed=25885757; DOI=10.1186/s12883-015-0290-8;
RA   Li X., Yao S., Xiang Y., Zhang X., Wu X., Luo L., Huang H., Zhu M., Wan H.,
RA   Hong D.;
RT   "The clinical and genetic features in a cohort of mainland Chinese patients
RT   with thyrotoxic periodic paralysis.";
RL   BMC Neurol. 15:38-38(2015).
RN   [7]
RP   VARIANT ARG-169, CHARACTERIZATION OF VARIANT ARG-169, AND CHARACTERIZATION
RP   OF VARIANTS TTPP2 126-GLN--HIS-344 DEL; THR-360 AND LYS-388.
RX   PubMed=27178871; DOI=10.1016/j.clinph.2016.03.008;
RA   Zheng J., Liang Z., Hou Y., Liu F., Hu Y., Lin P., Yan C.;
RT   "A novel Kir2.6 mutation associated with hypokalemic periodic paralysis.";
RL   Clin. Neurophysiol. 127:2503-2508(2016).
CC   -!- FUNCTION: Inward rectifier potassium channels are characterized by a
CC       greater tendency to allow potassium to flow into the cell rather than
CC       out of it. Their voltage dependence is regulated by the concentration
CC       of extracellular potassium; as external potassium is raised, the
CC       voltage range of the channel opening shifts to more positive voltages.
CC       The inward rectification is mainly due to the blockage of outward
CC       current by internal magnesium. {ECO:0000269|PubMed:20074522,
CC       ECO:0000269|PubMed:27008341}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=K(+)(in) = K(+)(out); Xref=Rhea:RHEA:29463, ChEBI:CHEBI:29103;
CC         Evidence={ECO:0000269|PubMed:20074522, ECO:0000269|PubMed:21209095,
CC         ECO:0000269|PubMed:21665951};
CC   -!- SUBUNIT: Can form heteromeric channels with Kir2.1/KCNJ2
CC       (PubMed:21209095). Can form heteromeric channels with Kir2.2/KCNJ12
CC       (PubMed:21209095). {ECO:0000269|PubMed:21209095}.
CC   -!- INTERACTION:
CC       B7U540; P50402: EMD; NbExp=3; IntAct=EBI-19949648, EBI-489887;
CC       B7U540; P63252: KCNJ2; NbExp=4; IntAct=EBI-19949648, EBI-703457;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21209095,
CC       ECO:0000269|PubMed:21665951}; Multi-pass membrane protein
CC       {ECO:0000255}. Endoplasmic reticulum {ECO:0000269|PubMed:21209095}.
CC   -!- TISSUE SPECIFICITY: Specifically expressed in skeletal muscle.
CC       {ECO:0000269|PubMed:20074522}.
CC   -!- INDUCTION: Up-regulated by triiodothyronine.
CC       {ECO:0000269|PubMed:20074522}.
CC   -!- PTM: Probably phosphorylated by PKC; decreases single-channel open
CC       probability. {ECO:0000269|PubMed:20074522}.
CC   -!- DISEASE: Thyrotoxic periodic paralysis 2 (TTPP2) [MIM:613239]: A
CC       sporadic muscular disorder characterized by episodic weakness and
CC       hypokalemia during a thyrotoxic state. It is clinically similar to
CC       hereditary hypokalemic periodic paralysis, except for the fact that
CC       hyperthyroidism is an absolute requirement for disease manifestation.
CC       The disease presents with recurrent episodes of acute muscular weakness
CC       of the four extremities that vary in severity from paresis to complete
CC       paralysis. Attacks are triggered by ingestion of a high carbohydrate
CC       load or strenuous physical activity followed by a period of rest.
CC       Thyrotoxic periodic paralysis can occur in association with any cause
CC       of hyperthyroidism, but is most commonly associated with Graves
CC       disease. {ECO:0000269|PubMed:20074522, ECO:0000269|PubMed:21665951,
CC       ECO:0000269|PubMed:25885757, ECO:0000269|PubMed:27178871}. Note=Disease
CC       susceptibility is associated with variants affecting the gene
CC       represented in this entry.
CC   -!- SIMILARITY: Belongs to the inward rectifier-type potassium channel
CC       (TC 1.A.2.1) family. KCNJ12 subfamily. {ECO:0000305}.
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DR   EMBL; FJ434338; ACJ64506.2; -; mRNA.
DR   EMBL; KT828539; AMQ11134.1; -; Genomic_DNA.
DR   EMBL; KT828540; AMQ11135.1; -; Genomic_DNA.
DR   EMBL; AC233702; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS74015.1; -.
DR   RefSeq; NP_001181887.2; NM_001194958.2.
DR   AlphaFoldDB; B7U540; -.
DR   SMR; B7U540; -.
DR   IntAct; B7U540; 4.
DR   STRING; 9606.ENSP00000457807; -.
DR   iPTMnet; B7U540; -.
DR   PhosphoSitePlus; B7U540; -.
DR   BioMuta; KCNJ18; -.
DR   jPOST; B7U540; -.
DR   MassIVE; B7U540; -.
DR   PaxDb; 9606-ENSP00000457807; -.
DR   PeptideAtlas; B7U540; -.
DR   Antibodypedia; 73068; 96 antibodies from 7 providers.
DR   DNASU; 100134444; -.
DR   Ensembl; ENST00000567955.3; ENSP00000457807.2; ENSG00000260458.3.
DR   GeneID; 100134444; -.
DR   KEGG; hsa:100134444; -.
DR   MANE-Select; ENST00000567955.3; ENSP00000457807.2; NM_001194958.2; NP_001181887.2.
DR   UCSC; uc032exz.1; human.
DR   AGR; HGNC:39080; -.
DR   CTD; 100134444; -.
DR   DisGeNET; 100134444; -.
DR   GeneCards; KCNJ18; -.
DR   HGNC; HGNC:39080; KCNJ18.
DR   HPA; ENSG00000260458; Tissue enriched (skin).
DR   MalaCards; KCNJ18; -.
DR   MIM; 613236; gene.
DR   MIM; 613239; phenotype.
DR   neXtProt; NX_B7U540; -.
DR   OpenTargets; ENSG00000260458; -.
DR   Orphanet; 79102; Thyrotoxic periodic paralysis.
DR   VEuPathDB; HostDB:ENSG00000260458; -.
DR   eggNOG; KOG3827; Eukaryota.
DR   GeneTree; ENSGT01030000234586; -.
DR   InParanoid; B7U540; -.
DR   OMA; CNIAFAN; -.
DR   OrthoDB; 273257at2759; -.
DR   PhylomeDB; B7U540; -.
DR   PathwayCommons; B7U540; -.
DR   SignaLink; B7U540; -.
DR   BioGRID-ORCS; 100134444; 8 hits in 218 CRISPR screens.
DR   GenomeRNAi; 100134444; -.
DR   Pharos; B7U540; Tbio.
DR   PRO; PR:B7U540; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; B7U540; protein.
DR   Bgee; ENSG00000260458; Expressed in skin of abdomen and 14 other cell types or tissues.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0034702; C:monoatomic ion channel complex; IEA:UniProtKB-KW.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0005242; F:inward rectifier potassium channel activity; IDA:UniProtKB.
DR   GO; GO:1990573; P:potassium ion import across plasma membrane; IBA:GO_Central.
DR   GO; GO:0034765; P:regulation of monoatomic ion transmembrane transport; IBA:GO_Central.
DR   FunFam; 1.10.287.70:FF:000039; ATP-sensitive inward rectifier potassium channel 12; 1.
DR   FunFam; 2.60.40.1400:FF:000001; G protein-activated inward rectifier potassium channel 2; 1.
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; IPR003272; K_chnl_inward-rec_Kir2.2.
DR   InterPro; IPR013518; K_chnl_inward-rec_Kir_cyto.
DR   InterPro; IPR013673; K_chnl_inward-rec_Kir_N.
DR   InterPro; IPR040445; Kir_TM.
DR   PANTHER; PTHR11767:SF14; ATP-SENSITIVE INWARD RECTIFIER POTASSIUM CHANNEL 12-RELATED; 1.
DR   PANTHER; PTHR11767; INWARD RECTIFIER POTASSIUM CHANNEL; 1.
DR   Pfam; PF01007; IRK; 1.
DR   Pfam; PF17655; IRK_C; 1.
DR   Pfam; PF08466; IRK_N; 1.
DR   PRINTS; PR01325; KIR22CHANNEL.
DR   PRINTS; PR01320; KIRCHANNEL.
DR   SUPFAM; SSF81296; E set domains; 1.
DR   SUPFAM; SSF81324; Voltage-gated potassium channels; 1.
PE   1: Evidence at protein level;
KW   Cell membrane; Disease variant; Endoplasmic reticulum; Ion channel;
KW   Ion transport; Membrane; Phosphoprotein; Potassium; Potassium transport;
KW   Reference proteome; Transmembrane; Transmembrane helix; Transport;
KW   Voltage-gated channel.
FT   CHAIN           1..433
FT                   /note="Inward rectifier potassium channel 18"
FT                   /id="PRO_0000395171"
FT   TOPO_DOM        1..77
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   TRANSMEM        78..104
FT                   /note="Helical; Name=M1"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   TOPO_DOM        105..129
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   INTRAMEM        130..146
FT                   /note="Helical; Pore-forming; Name=H5"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   TOPO_DOM        147..155
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   TRANSMEM        156..183
FT                   /note="Helical; Name=M2"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   TOPO_DOM        184..433
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   REGION          387..433
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           143..148
FT                   /note="Selectivity filter"
FT                   /evidence="ECO:0000250|UniProtKB:F1NHE9"
FT   COMPBIAS        396..414
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VARIANT         39..40
FT                   /note="RR -> QH"
FT                   /evidence="ECO:0000269|PubMed:20074522,
FT                   ECO:0000269|PubMed:27008341"
FT                   /id="VAR_079830"
FT   VARIANT         43
FT                   /note="R -> C (found in a patient with sporadic periodic
FT                   paralysis; uncertain significance; decreases potassium
FT                   inward and outward currents density; reduces cell surface
FT                   abundance; reduces conductance; dominant negative mutation;
FT                   dbSNP:rs527236151)"
FT                   /evidence="ECO:0000269|PubMed:21665951"
FT                   /id="VAR_079831"
FT   VARIANT         56
FT                   /note="A -> E (in dbSNP:rs1435508633)"
FT                   /evidence="ECO:0000269|PubMed:27008341"
FT                   /id="VAR_079832"
FT   VARIANT         126..344
FT                   /note="Missing (in TTPP2; abolishes potassium inward and
FT                   outward currents density)"
FT                   /evidence="ECO:0000269|PubMed:25885757,
FT                   ECO:0000269|PubMed:27178871"
FT                   /id="VAR_079833"
FT   VARIANT         140
FT                   /note="T -> M (in TTPP2; dbSNP:rs527236152)"
FT                   /evidence="ECO:0000269|PubMed:20074522"
FT                   /id="VAR_063286"
FT   VARIANT         168
FT                   /note="V -> M (in TTPP2; uncertain significance; decreases
FT                   potassium inward and outward currents density; reduces cell
FT                   surface abundance; reduces open propability; dominant
FT                   negative mutation; dbSNP:rs527236154)"
FT                   /evidence="ECO:0000269|PubMed:21665951"
FT                   /id="VAR_079834"
FT   VARIANT         169
FT                   /note="G -> R (found in a patient with hypokalemic periodic
FT                   paralysis without hyperthyroidism; reduces potassium inward
FT                   and outward currents density; dbSNP:rs1311839715)"
FT                   /evidence="ECO:0000269|PubMed:27178871"
FT                   /id="VAR_079835"
FT   VARIANT         200
FT                   /note="A -> P (found in a patient with sporadic periodic
FT                   paralysis; uncertain significance; abolishes potassium
FT                   inward and outward currents density; reduces cell surface
FT                   abundance; dbSNP:rs527236155)"
FT                   /evidence="ECO:0000269|PubMed:21665951"
FT                   /id="VAR_079836"
FT   VARIANT         205
FT                   /note="R -> H (in TTPP2; hypermorphic; longer time required
FT                   for half-maximal current degradation; dbSNP:rs672601244)"
FT                   /evidence="ECO:0000269|PubMed:20074522"
FT                   /id="VAR_063287"
FT   VARIANT         249
FT                   /note="I -> V (in dbSNP:rs1182398045)"
FT                   /evidence="ECO:0000269|PubMed:20074522,
FT                   ECO:0000269|PubMed:27008341"
FT                   /id="VAR_079837"
FT   VARIANT         354
FT                   /note="T -> M (in TTPP2; small decrease in current density;
FT                   dbSNP:rs527236158)"
FT                   /evidence="ECO:0000269|PubMed:20074522"
FT                   /id="VAR_063288"
FT   VARIANT         360
FT                   /note="K -> T (in TTPP2; abolishes potassium inward and
FT                   outward currents density)"
FT                   /evidence="ECO:0000269|PubMed:25885757,
FT                   ECO:0000269|PubMed:27178871"
FT                   /id="VAR_079838"
FT   VARIANT         366
FT                   /note="K -> R (in TTPP2; hypermorphic; longer time required
FT                   for half-maximal current degradation; dbSNP:rs527236159)"
FT                   /evidence="ECO:0000269|PubMed:20074522"
FT                   /id="VAR_063289"
FT   VARIANT         388
FT                   /note="E -> K (in TTPP2; reduces potassium inward and
FT                   outward currents density; dbSNP:rs1960793684)"
FT                   /evidence="ECO:0000269|PubMed:25885757,
FT                   ECO:0000269|PubMed:27178871"
FT                   /id="VAR_079839"
FT   MUTAGEN         156
FT                   /note="L->P: Increased expression at the cell membrane."
FT                   /evidence="ECO:0000269|PubMed:21209095"
FT   MUTAGEN         354
FT                   /note="T->E: Decreases the single-channel open probability
FT                   (Po) without altering its conductance."
FT                   /evidence="ECO:0000269|PubMed:20074522"
FT   CONFLICT        6
FT                   /note="R -> Q (in Ref. 1; ACJ64506)"
FT   CONFLICT        29
FT                   /note="N -> K (in Ref. 1; ACJ64506)"
FT   CONFLICT        192
FT                   /note="Q -> H (in Ref. 1; ACJ64506 and 2;
FT                   AMQ11134/AMQ11135)"
FT   CONFLICT        281
FT                   /note="F -> L (in Ref. 1; ACJ64506)"
FT   CONFLICT        338..342
FT                   /note="YKIDY -> FKIDH (in Ref. 1; ACJ64506)"
SQ   SEQUENCE   433 AA;  48880 MW;  284FC956E6139DD0 CRC64;
     MTAASRANPY SIVSLEEDGL HLVTMSGANG FGNGKVHTRR RCRNRFVKKN GQCNIAFANM
     DEKSQRYLAD MFTTCVDIRW RYMLLIFSLA FLASWLLFGV IFWVIAVAHG DLEPAEGHGR
     TPCVMQVHGF MAAFLFSIET QTTIGYGLRC VTEECLVAVF MVVAQSIVGC IIDSFMIGAI
     MAKMARPKKR AQTLLFSHNA VVALRDGKLC LMWRVGNLRK SHIVEAHVRA QLIKPRVTEE
     GEYIPLDQID IDVGFDKGLD RIFLVSPITI LHEIDEASPL FGISRQDLET DDFEIVVILE
     GMVEATAMTT QARSSYLANE ILWGHRFEPV LFEEKNQYKI DYSHFHKTYE VPSTPRCSAK
     DLVENKFLLP SANSFCYENE LAFLSRDEED EADGDQDGRS RDGLSPQARH DFDRLQAGGG
     VLEQRPYRRG SEI
//