KCJ18_HUMAN
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 03-AUG-2022, entry version 98.
DE RecName: Full=Inward rectifier potassium channel 18;
DE AltName: Full=Inward rectifier K(+) channel Kir2.6;
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, INDUCTION BY TRIIODOTHYRONINE, TISSUE
RP SPECIFICITY, PHOSPHORYLATION, VARIANTS TTPP2 MET-140; HIS-205; MET-354 AND
RP ARG-366, CHARACTERIZATION OF VARIANTS TTPP2 HIS-205; MET-354 AND ARG-366,
RP MUTAGENESIS OF THR-354, AND VARIANTS 39-ARG-ARG-40 DELINS GLN-HIS AND
RP 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 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, AND
RP 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 [5]
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 [6]
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 -!- 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:21665951};
CC Multi-pass membrane protein {ECO:0000255}.
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 (TC
CC 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; 3.
DR STRING; 9606.ENSP00000457807; -.
DR iPTMnet; B7U540; -.
DR PhosphoSitePlus; B7U540; -.
DR BioMuta; KCNJ18; -.
DR MassIVE; B7U540; -.
DR PeptideAtlas; B7U540; -.
DR PRIDE; B7U540; -.
DR Antibodypedia; 73068; 48 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 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; QYSYRRE; -.
DR OrthoDB; 956263at2759; -.
DR PhylomeDB; B7U540; -.
DR PathwayCommons; B7U540; -.
DR SignaLink; B7U540; -.
DR BioGRID-ORCS; 100134444; 8 hits in 170 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 tissues.
DR GO; GO:0016021; C:integral component of membrane; 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 ion transmembrane transport; IBA:GO_Central.
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; 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; PTHR11767; 1.
DR PANTHER; PTHR11767:SF14; PTHR11767:SF14; 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; SSF81296; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disease variant; Ion channel; Ion transport; Membrane;
KW Phosphoprotein; Potassium; Potassium transport; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1..433
FT /note="Inward rectifier potassium channel 18"
FT /id="PRO_0000395171"
FT TOPO_DOM 1..84
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 85..105
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 106..156
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 157..177
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 178..433
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 387..433
FT /note="Disordered"
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; unknown pathological significance; decreases
FT potassium inward and outward currents density; reduces cell
FT surface abundance; reduces conductance; dominant negative
FT mutation; 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; unknown pathological significance;
FT decreases potassium inward and outward currents density;
FT reduces cell surface abundance; reduces open propability;
FT dominant 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; unknown pathological significance; abolishes
FT potassium inward and outward currents density; reduces cell
FT surface 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)"
FT /evidence="ECO:0000269|PubMed:25885757,
FT ECO:0000269|PubMed:27178871"
FT /id="VAR_079839"
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; AMQ11134/
FT 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
