P48544 (IRK5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	419 AA.
Sequence status	Complete.
Protein existence	Evidence 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]

Ontologies

Keywords
Biological process	Ion transport Potassium transport Transport
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Long QT syndrome
Domain	Transmembrane Transmembrane helix
Ligand	Potassium
Molecular function	Ion channel Voltage-gated channel
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	synaptic transmission Traceable author statement. Source: Reactome
Cellular_component	voltage-gated potassium channel complex Traceable author statement Ref.6. Source: ProtInc
Molecular_function	G-protein activated inward rectifier potassium channel activity Traceable author statement Ref.6. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 419	419	G protein-activated inward rectifier potassium channel 4		PRO_0000154934
Regions
	Topological domain	1 – 86	86	Cytoplasmic By similarity
	Transmembrane	87 – 111	25	Helical; Name=M1; By similarity
	Topological domain	112 – 135	24	Extracellular By similarity
	Intramembrane	136 – 147	12	Helical; Pore-forming; Name=H5; By similarity
	Intramembrane	148 – 154	7	Pore-forming; By similarity
	Topological domain	155 – 163	9	Extracellular By similarity
	Transmembrane	164 – 185	22	Helical; Name=M2; By similarity
	Topological domain	186 – 419	234	Cytoplasmic By similarity
	Motif	149 – 154	6	Selectivity filter By similarity
Sites
	Site	179	1	Role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium By similarity
Natural variations
	Natural variant	39	1	R → H. Ref.10		VAR_065929
	Natural variant	145	1	E → Q Found in aldosterone-producing adrenal adenoma samples; somatic mutation. Ref.14		VAR_069182
	Natural variant	151	1	G → 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 variant	151	1	G → 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 variant	158	1	T → A in FH3; also found in aldosterone-producing adrenal adenoma. Ref.10 Ref.12		VAR_065931
	Natural variant	168	1	L → 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 variant	210	1	M → I. Ref.10 Corresponds to variant rs138295501 [ dbSNP | Ensembl ].		VAR_065933
	Natural variant	282	1	Q → E. Ref.1 Ref.2 Ref.4 Ref.5 Ref.6 Ref.9 Corresponds to variant rs7102584 [ dbSNP | Ensembl ].		VAR_063107
	Natural variant	387	1	G → R in LQT13. Ref.11		VAR_063766
Experimental info
	Sequence conflict	35	1	I → T in AAB07045. Ref.5
	Sequence conflict	388	1	G → R in CAA58565. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P48544 [UniParc]. Last modified May 18, 2010. Version 2. Checksum: 7C14A6B0B7EA0FD4	FASTA	419	47,668
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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. , 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. , 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. , 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.
IPI	IPI00298865.
PIR	G02232.
RefSeq	NP_000881.3. NM_000890.3.
UniGene	Hs.632109.
3D structure databases
ProteinModelPortal	P48544.
SMR	P48544. Positions 51-370.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-90031.
STRING	9606.ENSP00000339960.
Protein family/group databases
TCDB	1.A.2.1.3. inward rectifier K+ channel (IRK-C) family.
PTM databases
PhosphoSite	P48544.
Polymorphism databases
DMDM	296434543.
Proteomic databases
PaxDb	P48544.
PRIDE	P48544.
Protocols and materials databases
DNASU	3762.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000338350; ENSP00000339960; ENSG00000120457. ENST00000529694; ENSP00000433295; ENSG00000120457. ENST00000533599; ENSP00000434266; ENSG00000120457.
GeneID	3762.
KEGG	hsa:3762.
UCSC	uc001qet.3. human.
Organism-specific databases
CTD	3762.
GeneCards	GC11P128760.
HGNC	HGNC:6266. KCNJ5.
HPA	CAB022569. HPA014722. HPA017353.
MIM	600734. gene. 613485. phenotype. 613677. phenotype.
neXtProt	NX_P48544.
Orphanet	251274. Familial hyperaldosteronism type 3. 101016. Romano-Ward syndrome.
PharmGKB	PA216.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG72812.
HOGENOM	HOG000237325.
HOVERGEN	HBG006178.
InParanoid	P48544.
KO	K04999.
OMA	QARSSYM.
OrthoDB	EOG4VT5X9.
PhylomeDB	P48544.
Enzyme and pathway databases
Reactome	REACT_13685. Neuronal System.
Gene expression databases
ArrayExpress	P48544.
Bgee	P48544.
CleanEx	HS_KCNJ5.
Genevestigator	P48544.
GermOnline	ENSG00000120457. Homo sapiens.
Family and domain databases
Gene3D	2.60.40.1400. 1 hit.
InterPro	IPR014756. 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]
PANTHER	PTHR11767. PTHR11767. 1 hit.
Pfam	PF01007. IRK. 1 hit. [Graphical view]
PIRSF	PIRSF005465. GIRK_kir. 1 hit.
PRINTS	PR01330. KIR34CHANNEL. PR01320. KIRCHANNEL.
SUPFAM	SSF81296. Ig_E-set. 1 hit.
ProtoNet	Search...
Other
ChEMBL	CHEMBL1914278.
DrugBank	DB01016. Glibenclamide.
GenomeRNAi	3762.
NextBio	14751.
SOURCE	Search...

Entry information

Entry name

IRK5_HUMAN

Accession

Primary (citable) accession number: P48544
Secondary accession number(s): B2R744 , Q6DK13, Q6DK14, Q92807

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	May 18, 2010
Last modified:	May 29, 2013
This is version 133 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.