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P48544 (IRK5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
G protein-activated inward rectifier potassium channel 4

Short name=GIRK-4
Alternative name(s):
Cardiac inward rectifier
Short name=CIR
Heart KATP channel
Inward rectifier K(+) channel Kir3.4
Short name=IRK-4
KATP-1
Potassium channel, inwardly rectifying subfamily J member 5
Gene names
Name:KCNJ5
Synonyms:GIRK4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length419 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium.

Subunit structure

May associate with GIRK1 and GIRK2 to form a G-protein-activated heteromultimer pore-forming unit. The resulting inward current is much larger By similarity.

Subcellular location

Membrane; Multi-pass membrane protein.

Tissue specificity

Islets, exocrine pancreas and heart. Expressed in the adrenal cortex, particularly the zona glomerulosa. Ref.10

Involvement in disease

Long QT syndrome 13 (LQT13) [MIM:613485]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11

Familial hyperaldosteronism 3 (FH3) [MIM:613677]: A form of hyperaldosteronism characterized by hypertension secondary to massive adrenal mineralocorticoid production. Like patients with familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism), patients with FH3 present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. However, hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.12 Ref.15

Somatic mutations in KCNJ5 have been found in aldosterone-producing adrenal adenomas (APA) and can be responsible for aldosteronism associated with cell autonomous proliferation. APAs are typically solitary, well circumscribed tumors diagnosed between ages 30 and 70. They come to medical attention due to new or worsening hypertension, often with hypokalemia. The precise role of KCNJ5 mutations in APA is under debate. They produce increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. However, they may not be causative of APA development but may be a consequence of tumorigenesis, playing only a contributory role toward aldosterone overproduction and tumor growth (Ref.13). Somatic mutations in KCNJ5 have not been found in non-aldosterone secreting adrenal adenomas suggesting that they are specifically associated with APA (Ref.13 and Ref.14). Ref.10 Ref.12 Ref.13 Ref.14

Sequence similarities

Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ5 subfamily. [View classification]

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 419419G protein-activated inward rectifier potassium channel 4
PRO_0000154934

Regions

Topological domain1 – 8686Cytoplasmic By similarity
Transmembrane87 – 11125Helical; Name=M1; By similarity
Topological domain112 – 13524Extracellular By similarity
Intramembrane136 – 14712Helical; Pore-forming; Name=H5; By similarity
Intramembrane148 – 1547Pore-forming; By similarity
Topological domain155 – 1639Extracellular By similarity
Transmembrane164 – 18522Helical; Name=M2; By similarity
Topological domain186 – 419234Cytoplasmic By similarity
Motif149 – 1546Selectivity filter By similarity

Sites

Site1791Role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium By similarity

Natural variations

Natural variant391R → H. Ref.10
VAR_065929
Natural variant1451E → Q Found in aldosterone-producing adrenal adenoma samples; somatic mutation. Ref.14
VAR_069182
Natural variant1511G → E in FH3; results in a profound alteration of channel function with loss of channel selectivity and membrane depolarization. Ref.12 Ref.15
VAR_067090
Natural variant1511G → R in FH3 and APA; detected as germline mutation in a kindred with severe primary aldosteronism and adrenocortical hyperplasia; recurrent mutation in APA; somatic mutation; results in loss of channel selectivity and membrane depolarization. Ref.10 Ref.12 Ref.13 Ref.14 Ref.15
VAR_065930
Natural variant1581T → A in FH3; also found in aldosterone-producing adrenal adenoma. Ref.10 Ref.12
VAR_065931
Natural variant1681L → R in APA; somatic mutation; recurrent mutation; results in loss of channel selectivity and membrane depolarization. Ref.10 Ref.12 Ref.13 Ref.14
VAR_065932
Natural variant2101M → I. Ref.10
Corresponds to variant rs138295501 [ dbSNP | Ensembl ].
VAR_065933
Natural variant2821Q → E. Ref.1 Ref.2 Ref.4 Ref.5 Ref.6 Ref.9
Corresponds to variant rs7102584 [ dbSNP | Ensembl ].
VAR_063107
Natural variant3871G → R in LQT13. Ref.11
Corresponds to variant rs199830292 [ dbSNP | Ensembl ].
VAR_063766

Experimental info

Sequence conflict351I → T in AAB07045. Ref.5
Sequence conflict3881G → R in CAA58565. Ref.2

Sequences

Sequence LengthMass (Da)Tools
P48544 [UniParc].

Last modified May 18, 2010. Version 2.
Checksum: 7C14A6B0B7EA0FD4

FASTA41947,668
        10         20         30         40         50         60 
MAGDSRNAMN QDMEIGVTPW DPKKIPKQAR DYVPIATDRT RLLAEGKKPR QRYMEKSGKC 

        70         80         90        100        110        120 
NVHHGNVQET YRYLSDLFTT LVDLKWRFNL LVFTMVYTVT WLFFGFIWWL IAYIRGDLDH 

       130        140        150        160        170        180 
VGDQEWIPCV ENLSGFVSAF LFSIETETTI GYGFRVITEK CPEGIILLLV QAILGSIVNA 

       190        200        210        220        230        240 
FMVGCMFVKI SQPKKRAETL MFSNNAVISM RDEKLCLMFR VGDLRNSHIV EASIRAKLIK 

       250        260        270        280        290        300 
SRQTKEGEFI PLNQTDINVG FDTGDDRLFL VSPLIISHEI NQKSPFWEMS QAQLHQEEFE 

       310        320        330        340        350        360 
VVVILEGMVE ATGMTCQARS SYMDTEVLWG HRFTPVLTLE KGFYEVDYNT FHDTYETNTP 

       370        380        390        400        410 
SCCAKELAEM KREGRLLQYL PSPPLLGGCA EAGLDAEAEQ NEEDEPKGLG GSREARGSV 

« Hide

References

« Hide 'large scale' references
[1]Chan K.W., Langan M.N., Sui J., Kozak A., Pabon A., Ladias J.A.A., Logothetis D.E.
Submitted (OCT-1995) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLU-282.
Tissue: Pancreas.
[2]"Cloning and functional expression of a rat heart KATP channel."
Ashford M.L.J., Bond C.T., Blair T.A., Adelman J.P.
Nature 370:456-459(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLU-282.
[3]Erratum
Ashford M.L.J., Bond C.T., Blair T.A., Adelman J.P.
Nature 378:792-792(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: RETRACTION.
[4]"A G-protein-activated inwardly rectifying K+ channel (GIRK4) from human hippocampus associates with other GIRK channels."
Spauschus A., Lentes K.U., Wischmeyer E., Dissmann E., Karschin C., Karschin A.
J. Neurosci. 16:930-938(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLU-282.
[5]"Co-expression of human Kir3 subunits can yield channels with different functional properties."
Schoots O., Wilson J.M., Ethier N., Bigras E., Hebert T.E., Van Tol H.H.M.
Cell. Signal. 11:871-883(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLU-282.
Tissue: Pituitary.
[6]"Functional characterization and localization of a cardiac-type inwardly rectifying K+ channel."
Iizuka M., Kubo Y., Tsunenari I., Pan C.X., Akiba I., Kono T.
Recept. Channels 3:299-315(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLU-282.
Tissue: Heart.
[7]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Thymus.
[8]"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. expand/collapse author list , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT GLU-282.
Tissue: Lung.
[10]"K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension."
Choi M., Scholl U.I., Yue P., Bjorklund P., Zhao B., Nelson-Williams C., Ji W., Cho Y., Patel A., Men C.J., Lolis E., Wisgerhof M.V., Geller D.S., Mane S., Hellman P., Westin G., Akerstrom G., Wang W., Carling T., Lifton R.P.
Science 331:768-772(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, VARIANT FH3 ALA-158, VARIANTS APA ARG-151 AND ARG-168, CHARACTERIZATION OF VARIANTS APA ARG-151 AND ARG-168, VARIANTS HIS-39 AND ILE-210.
[11]"Identification of a Kir3.4 mutation in congenital long QT syndrome."
Yang Y., Yang Y., Liang B., Liu J., Li J., Grunnet M., Olesen S.P., Rasmussen H.B., Ellinor P.T., Gao L., Lin X., Li L., Wang L., Xiao J., Liu Y., Liu Y., Zhang S., Liang D. expand/collapse author list , Peng L., Jespersen T., Chen Y.H.
Am. J. Hum. Genet. 86:872-880(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT LQT13 ARG-387.
[12]"KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism."
Mulatero P., Tauber P., Zennaro M.C., Monticone S., Lang K., Beuschlein F., Fischer E., Tizzani D., Pallauf A., Viola A., Amar L., Williams T.A., Strom T.M., Graf E., Bandulik S., Penton D., Plouin P.F., Warth R. expand/collapse author list , Allolio B., Jeunemaitre X., Veglio F., Reincke M.
Hypertension 59:235-240(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS APA ARG-151 AND ARG-168, VARIANTS FH3 GLU-151 AND ALA-158, CHARACTERIZATION OF VARIANT FH3 GLU-151.
[13]"Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism."
Boulkroun S., Beuschlein F., Rossi G.P., Golib-Dzib J.F., Fischer E., Amar L., Mulatero P., Samson-Couterie B., Hahner S., Quinkler M., Fallo F., Letizia C., Allolio B., Ceolotto G., Cicala M.V., Lang K., Lefebvre H., Lenzini L. expand/collapse author list , Maniero C., Monticone S., Perrocheau M., Pilon C., Plouin P.F., Rayes N., Seccia T.M., Veglio F., Williams T.A., Zinnamosca L., Mantero F., Benecke A., Jeunemaitre X., Reincke M., Zennaro M.C.
Hypertension 59:592-598(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS APA ARG-151 AND ARG-168.
[14]"Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter."
Akerstrom T., Crona J., Delgado Verdugo A., Starker L.F., Cupisti K., Willenberg H.S., Knoefel W.T., Saeger W., Feller A., Ip J., Soon P., Anlauf M., Alesina P.F., Schmid K.W., Decaussin M., Levillain P., Wangberg B., Peix J.L. expand/collapse author list , Robinson B., Zedenius J., Backdahl M., Caramuta S., Iwen K.A., Botling J., Stalberg P., Kraimps J.L., Dralle H., Hellman P., Sidhu S., Westin G., Lehnert H., Walz M.K., Akerstrom G., Carling T., Choi M., Lifton R.P., Bjorklund P.
PLoS ONE 7:E41926-E41926(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS APA ARG-151 AND ARG-168, VARIANT GLN-145.
[15]"Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5."
Scholl U.I., Nelson-Williams C., Yue P., Grekin R., Wyatt R.J., Dillon M.J., Couch R., Hammer L.K., Harley F.L., Farhi A., Wang W.H., Lifton R.P.
Proc. Natl. Acad. Sci. U.S.A. 109:2533-2538(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS FH3 ARG-151 AND GLU-151.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U39195 mRNA. Translation: AAB53093.1.
X83582 mRNA. Translation: CAA58565.1.
L47208 mRNA. Translation: AAB07269.1.
U52154 mRNA. Translation: AAB07045.1.
D50134 mRNA. Translation: BAA08814.1.
AP000920 Genomic DNA. No translation available.
AK312837 mRNA. Translation: BAG35691.1.
BC069571 mRNA. Translation: AAH69571.1.
BC074838 mRNA. Translation: AAH74838.2.
BC069386 mRNA. Translation: AAH69386.1.
BC069482 mRNA. Translation: AAH69482.1.
BC069499 mRNA. Translation: AAH69499.1.
BC074839 mRNA. Translation: AAH74839.2.
PIRG02232.
RefSeqNP_000881.3. NM_000890.3.
XP_005271600.1. XM_005271543.1.
UniGeneHs.444595.
Hs.632109.

3D structure databases

ProteinModelPortalP48544.
SMRP48544. Positions 51-370.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109964. 4 interactions.
MINTMINT-90031.
STRING9606.ENSP00000339960.

Chemistry

DrugBankDB01016. Glibenclamide.
GuidetoPHARMACOLOGY437.

Protein family/group databases

TCDB1.A.2.1.3. inward rectifier k(+) channel (irk-c) family.

PTM databases

PhosphoSiteP48544.

Polymorphism databases

DMDM296434543.

Proteomic databases

PaxDbP48544.
PRIDEP48544.

Protocols and materials databases

DNASU3762.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000338350; ENSP00000339960; ENSG00000120457.
ENST00000529694; ENSP00000433295; ENSG00000120457.
ENST00000533599; ENSP00000434266; ENSG00000120457.
GeneID3762.
KEGGhsa:3762.
UCSCuc001qet.3. human.

Organism-specific databases

CTD3762.
GeneCardsGC11P128760.
HGNCHGNC:6266. KCNJ5.
HPACAB022569.
HPA014722.
HPA017353.
MIM600734. gene.
613485. phenotype.
613677. phenotype.
neXtProtNX_P48544.
Orphanet85142. Aldosterone-producing adenoma.
251274. Familial hyperaldosteronism type 3.
101016. Romano-Ward syndrome.
PharmGKBPA216.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG72812.
HOGENOMHOG000237325.
HOVERGENHBG006178.
InParanoidP48544.
KOK04999.
OMAQARSSYM.
OrthoDBEOG7XPZ5K.
PhylomeDBP48544.
TreeFamTF313676.

Enzyme and pathway databases

ReactomeREACT_13685. Neuronal System.

Gene expression databases

ArrayExpressP48544.
BgeeP48544.
CleanExHS_KCNJ5.
GenevestigatorP48544.

Family and domain databases

Gene3D2.60.40.1400. 1 hit.
InterProIPR014756. Ig_E-set.
IPR016449. K_chnl_inward-rec_Kir.
IPR003277. K_chnl_inward-rec_Kir3.4.
IPR013518. K_chnl_inward-rec_Kir_cyto.
[Graphical view]
PANTHERPTHR11767. PTHR11767. 1 hit.
PfamPF01007. IRK. 1 hit.
[Graphical view]
PIRSFPIRSF005465. GIRK_kir. 1 hit.
PRINTSPR01330. KIR34CHANNEL.
PR01320. KIRCHANNEL.
SUPFAMSSF81296. SSF81296. 1 hit.
ProtoNetSearch...

Other

GeneWikiKCNJ5.
GenomeRNAi3762.
NextBio14751.
PROP48544.
SOURCESearch...

Entry information

Entry nameIRK5_HUMAN
AccessionPrimary (citable) accession number: P48544
Secondary accession number(s): B2R744 expand/collapse secondary AC list , Q6DK13, Q6DK14, Q92807
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: May 18, 2010
Last modified: April 16, 2014
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM