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Protein

G protein-activated inward rectifier potassium channel 4

Gene

KCNJ5

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei179Role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesiumBy similarity1

GO - Molecular functioni

GO - Biological processi

  • membrane repolarization during atrial cardiac muscle cell action potential Source: BHF-UCL
  • potassium ion import Source: BHF-UCL
  • potassium ion import across plasma membrane Source: BHF-UCL
  • potassium ion transport Source: ProtInc
  • regulation of heart rate by cardiac conduction Source: BHF-UCL
  • ventricular cardiac muscle cell membrane repolarization Source: BHF-UCL

Keywordsi

Molecular functionIon channel, Voltage-gated channel
Biological processIon transport, Potassium transport, Transport
LigandPotassium

Enzyme and pathway databases

ReactomeiR-HSA-1296041. Activation of G protein gated Potassium channels.
R-HSA-997272. Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits.
SIGNORiP48544.

Protein family/group databases

TCDBi1.A.2.1.3. inward rectifier k(+) channel (irk-c) family.

Names & Taxonomyi

Protein namesi
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 namesi
Name:KCNJ5
Synonyms:GIRK4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:6266. KCNJ5.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 86CytoplasmicBy similarityAdd BLAST86
Transmembranei87 – 111Helical; Name=M1By similarityAdd BLAST25
Topological domaini112 – 135ExtracellularBy similarityAdd BLAST24
Intramembranei136 – 147Helical; Pore-forming; Name=H5By similarityAdd BLAST12
Intramembranei148 – 154Pore-formingBy similarity7
Topological domaini155 – 163ExtracellularBy similarity9
Transmembranei164 – 185Helical; Name=M2By similarityAdd BLAST22
Topological domaini186 – 419CytoplasmicBy similarityAdd BLAST234

GO - Cellular componenti

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Involvement in diseasei

Long QT syndrome 13 (LQT13)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:613485
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_063766387G → R in LQT13. 1 PublicationCorresponds to variant dbSNP:rs199830292Ensembl.1
Hyperaldosteronism, familial, 3 (HALD3)9 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of hyperaldosteronism characterized by hypertension secondary to massive adrenal mineralocorticoid production. HALD3 patients present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension.
See also OMIM:613677
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067090151G → E in HALD3; results in a profound alteration of channel function with loss of channel selectivity and membrane depolarization. 3 PublicationsCorresponds to variant dbSNP:rs587777437Ensembl.1
Natural variantiVAR_065930151G → R in HALD3; detected as germline mutation in a kindred with severe primary aldosteronism and adrenocortical hyperplasia; also found as somatic mutation in aldosterone-producing adrenal adenoma samples; results in loss of channel selectivity and membrane depolarization. 6 PublicationsCorresponds to variant dbSNP:rs386352319Ensembl.1
Natural variantiVAR_077577152Y → C in HALD3; results in alteration of channel function with reduced channel selectivity and membrane depolarization; increases expression of CYP11B2 and its transcriptional regulator NR4A2. 1 Publication1
Natural variantiVAR_077578157I → S in HALD3; loss of channel selectivity. 1 PublicationCorresponds to variant dbSNP:rs587777438Ensembl.1
Natural variantiVAR_065931158T → A in HALD3; also found in aldosterone-producing adrenal adenoma samples; results in loss of channel selectivity and membrane depolarization; increases expression of CYP11B2 and its transcriptional regulators NR4A2 and ATF2; increases aldosterone and hybrid steroids 18-oxocortisol and 18-hydroxycortisol synthesis; increases STAR expression and phosphorylation. 5 PublicationsCorresponds to variant dbSNP:rs387906778Ensembl.1
Somatic mutations in KCNJ5 have been found in aldosterone-producing adrenal adenomas 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 (PubMed:22275527). Somatic mutations in KCNJ5 have not been found in non-aldosterone secreting adrenal adenomas suggesting that they are specifically associated with APA (PubMed:22275527 and PubMed:22848660).4 Publications
Mutations in KCNJ5 are involved in the pathogenesis of hypertension without primary aldosteronism but with increased aldosterone response to ACTH stimulation.1 Publication

Keywords - Diseasei

Disease mutation, Long QT syndrome

Organism-specific databases

DisGeNETi3762.
MalaCardsiKCNJ5.
MIMi613485. phenotype.
613677. phenotype.
OpenTargetsiENSG00000120457.
Orphaneti85142. Aldosterone-producing adenoma.
37553. Cardiodysrhythmic potassium-sensitive periodic paralysis.
251274. Familial hyperaldosteronism type III.
101016. Romano-Ward syndrome.
PharmGKBiPA216.

Chemistry databases

ChEMBLiCHEMBL3038488.
DrugBankiDB00898. Ethanol.
DB01016. Glyburide.
GuidetoPHARMACOLOGYi437.

Polymorphism and mutation databases

BioMutaiKCNJ5.
DMDMi296434543.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001549341 – 419G protein-activated inward rectifier potassium channel 4Add BLAST419

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei5PhosphoserineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP48544.
PaxDbiP48544.
PeptideAtlasiP48544.
PRIDEiP48544.

PTM databases

iPTMnetiP48544.
PhosphoSitePlusiP48544.

Expressioni

Tissue specificityi

Islets, exocrine pancreas and heart. Expressed in the adrenal cortex, particularly the zona glomerulosa.1 Publication

Gene expression databases

BgeeiENSG00000120457.
CleanExiHS_KCNJ5.
GenevisibleiP48544. HS.

Organism-specific databases

HPAiCAB022569.
HPA014722.
HPA017353.

Interactioni

Subunit structurei

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

Protein-protein interaction databases

BioGridi109964. 16 interactors.
MINTiMINT-90031.
STRINGi9606.ENSP00000339960.

Chemistry databases

BindingDBiP48544.

Structurei

3D structure databases

ProteinModelPortaliP48544.
SMRiP48544.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi149 – 154Selectivity filterBy similarity6

Sequence similaritiesi

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3827. Eukaryota.
ENOG410XQ62. LUCA.
GeneTreeiENSGT00760000118842.
HOGENOMiHOG000237325.
HOVERGENiHBG006178.
InParanoidiP48544.
KOiK04999.
OMAiMEKSGKC.
OrthoDBiEOG091G08HC.
PhylomeDBiP48544.
TreeFamiTF313676.

Family and domain databases

Gene3Di2.60.40.1400. 1 hit.
InterProiView protein in 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.
PANTHERiPTHR11767. PTHR11767. 1 hit.
PfamiView protein in Pfam
PF01007. IRK. 1 hit.
PIRSFiPIRSF005465. GIRK_kir. 1 hit.
PRINTSiPR01330. KIR34CHANNEL.
PR01320. KIRCHANNEL.
SUPFAMiSSF81296. SSF81296. 1 hit.

Sequencei

Sequence statusi: Complete.

P48544-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAGDSRNAMN QDMEIGVTPW DPKKIPKQAR DYVPIATDRT RLLAEGKKPR
60 70 80 90 100
QRYMEKSGKC NVHHGNVQET YRYLSDLFTT LVDLKWRFNL LVFTMVYTVT
110 120 130 140 150
WLFFGFIWWL IAYIRGDLDH VGDQEWIPCV ENLSGFVSAF LFSIETETTI
160 170 180 190 200
GYGFRVITEK CPEGIILLLV QAILGSIVNA FMVGCMFVKI SQPKKRAETL
210 220 230 240 250
MFSNNAVISM RDEKLCLMFR VGDLRNSHIV EASIRAKLIK SRQTKEGEFI
260 270 280 290 300
PLNQTDINVG FDTGDDRLFL VSPLIISHEI NQKSPFWEMS QAQLHQEEFE
310 320 330 340 350
VVVILEGMVE ATGMTCQARS SYMDTEVLWG HRFTPVLTLE KGFYEVDYNT
360 370 380 390 400
FHDTYETNTP SCCAKELAEM KREGRLLQYL PSPPLLGGCA EAGLDAEAEQ
410
NEEDEPKGLG GSREARGSV
Length:419
Mass (Da):47,668
Last modified:May 18, 2010 - v2
Checksum:i7C14A6B0B7EA0FD4
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti35I → T in AAB07045 (PubMed:10659995).Curated1
Sequence conflicti388G → R in CAA58565 (PubMed:8047164).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06592939R → H1 PublicationCorresponds to variant dbSNP:rs560269341Ensembl.1
Natural variantiVAR_069182145E → Q Found in aldosterone-producing adrenal adenoma samples; somatic mutation. 1 Publication1
Natural variantiVAR_067090151G → E in HALD3; results in a profound alteration of channel function with loss of channel selectivity and membrane depolarization. 3 PublicationsCorresponds to variant dbSNP:rs587777437Ensembl.1
Natural variantiVAR_065930151G → R in HALD3; detected as germline mutation in a kindred with severe primary aldosteronism and adrenocortical hyperplasia; also found as somatic mutation in aldosterone-producing adrenal adenoma samples; results in loss of channel selectivity and membrane depolarization. 6 PublicationsCorresponds to variant dbSNP:rs386352319Ensembl.1
Natural variantiVAR_077577152Y → C in HALD3; results in alteration of channel function with reduced channel selectivity and membrane depolarization; increases expression of CYP11B2 and its transcriptional regulator NR4A2. 1 Publication1
Natural variantiVAR_077578157I → S in HALD3; loss of channel selectivity. 1 PublicationCorresponds to variant dbSNP:rs587777438Ensembl.1
Natural variantiVAR_065931158T → A in HALD3; also found in aldosterone-producing adrenal adenoma samples; results in loss of channel selectivity and membrane depolarization; increases expression of CYP11B2 and its transcriptional regulators NR4A2 and ATF2; increases aldosterone and hybrid steroids 18-oxocortisol and 18-hydroxycortisol synthesis; increases STAR expression and phosphorylation. 5 PublicationsCorresponds to variant dbSNP:rs387906778Ensembl.1
Natural variantiVAR_065932168L → R Found in aldosterone-producing adrenal adenoma samples; somatic mutation; results in loss of channel selectivity and membrane depolarization. 5 PublicationsCorresponds to variant dbSNP:rs386352318Ensembl.1
Natural variantiVAR_065933210M → I1 PublicationCorresponds to variant dbSNP:rs138295501Ensembl.1
Natural variantiVAR_077579259V → M Found in patients with hypertension with ACTH-dependent aldosterone hypersecretion; unknown pathological significance; no effect on channel funciton. 1 PublicationCorresponds to variant dbSNP:rs759363415Ensembl.1
Natural variantiVAR_063107282Q → E6 PublicationsCorresponds to variant dbSNP:rs7102584Ensembl.1
Natural variantiVAR_077580348Y → N Probable disease-associated mutation found in patients with hypertension with ACTH-dependent aldosterone hypersecretion; loss of channel selectivity. 1 Publication1
Natural variantiVAR_063766387G → R in LQT13. 1 PublicationCorresponds to variant dbSNP:rs199830292Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS8479.1.
PIRiG02232.
RefSeqiNP_000881.3. NM_000890.3.
XP_011541111.1. XM_011542809.2.
XP_011541112.1. XM_011542810.2.
UniGeneiHs.444595.
Hs.632109.

Genome annotation databases

EnsembliENST00000338350; ENSP00000339960; ENSG00000120457.
ENST00000529694; ENSP00000433295; ENSG00000120457.
ENST00000533599; ENSP00000434266; ENSG00000120457.
GeneIDi3762.
KEGGihsa:3762.
UCSCiuc001qet.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiKCNJ5_HUMAN
AccessioniPrimary (citable) accession number: P48544
Secondary accession number(s): B2R744
, Q6DK13, Q6DK14, Q92807
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: May 18, 2010
Last modified: June 7, 2017
This is version 171 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families