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Kir2.1

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Target id: 430

Nomenclature: Kir2.1

Family: Inwardly rectifying potassium channels (KIR)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 1 427 17q24.3 KCNJ2 potassium inwardly rectifying channel subfamily J member 2 22
Mouse 2 1 428 11 75.23 cM Kcnj2 potassium inwardly-rectifying channel, subfamily J, member 2 10
Rat 2 1 427 10q32.1 Kcnj2 potassium inwardly-rectifying channel, subfamily J, member 2 30
Previous and Unofficial Names Click here for help
potassium inwardly rectifying channel subfamily J member 2 | IRK1 | Kcnf1 | potassium channel, inwardly rectifying subfamily J, member 2 | potassium inwardly-rectifying channel | potassium voltage-gated channel subfamily J member 2 | RBL-IRK1
Database Links Click here for help
Alphafold P63252 (Hs), P35561 (Mm), Q64273 (Rn)
CATH/Gene3D 2.60.40.1400
ChEMBL Target CHEMBL1914276 (Hs), CHEMBL1293290 (Mm)
Ensembl Gene ENSG00000123700 (Hs), ENSMUSG00000041695 (Mm), ENSRNOG00000064933 (Rn)
Entrez Gene 3759 (Hs), 16518 (Mm), 29712 (Rn)
Human Protein Atlas ENSG00000123700 (Hs)
KEGG Gene hsa:3759 (Hs), mmu:16518 (Mm), rno:29712 (Rn)
OMIM 600681 (Hs)
Orphanet ORPHA122791 (Hs)
Pharos P63252 (Hs)
RefSeq Nucleotide NM_000891 (Hs), NM_008425 (Mm), NM_017296 (Rn)
RefSeq Protein NP_000882 (Hs), NP_032451 (Mm), NP_058992 (Rn)
UniProtKB P63252 (Hs), P35561 (Mm), Q64273 (Rn)
Wikipedia KCNJ2 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Kir2.x 19,25
Kir4.1 4
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
PSD-93/Chapsyn 110 14
Filamin-A 24
AKAP79 3
Veli-1 or Veli-3 11-12
CASK 11-12
SAP97 11-13
PSD95 17
Functional Characteristics Click here for help
IK1 in heart, ‘strong’ inward–rectifier current
Ion Selectivity and Conductance Click here for help
Species:  Mouse
Rank order:  K+ [21.0 pS]
References:  10

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
PIP2 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Mm Agonist - - 1x10-5 - 5x10-5 -30.0 7,23,27
⤷ Conc range: 1x10-5 - 5x10-5 M [7,23,27]
Holding voltage: -30.0 mV
Gating inhibitors Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
oleoyl-CoA Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Mm Antagonist - - 1.8x10-8 - 1x10-5 -135.0 – -100.0 23,26
⤷ Conc range: 1.8x10-8 - 1x10-5 M [23,26]
Holding voltage: -135.0 – -100.0 mV
Gating Inhibitor Comments
Gating is also inhibited by PKA and tyrosine kinase phosphorylation [28-29].
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
Rb+ Mm Antagonist - - 1x10-3 - 1x10-2 -130.0 – -50.0 1
⤷ Conc range: 1x10-3 - 1x10-2 M [1]
Holding voltage: -130.0 – -50.0 mV
spermine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Mm Antagonist 9.1 pKd - 40.0 8,31
⤷ pKd 9.1 [8,31]
Holding voltage: 40.0 mV
spermidine Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Mm Antagonist 8.1 pKd - 40.0 31
⤷ pKd 8.1 [31]
Holding voltage: 40.0 mV
putrescine Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Mm Antagonist 5.1 pKd - 40.0 8,31
⤷ pKd 5.1 [8,31]
Holding voltage: 40.0 mV
Intracellular Mg2+ Click here for species-specific activity table Ligand is endogenous in the given species Mm Antagonist 4.8 pKd - 40.0 31
⤷ pKd 4.8 (Kd 1.71x10-5 M) [31]
Holding voltage: 40.0 mV
Ba2+ Click here for species-specific activity table Mm Antagonist 3.9 – 5.6 pKd 1x10-6 - 1x10-4 0.0 – -80.0 2
⤷ pKd 3.9 – 5.6 Conc range: 1x10-6 - 1x10-4 M [2]
Holding voltage: 0.0 – -80.0 mV
Cs+ Click here for species-specific activity table Mm Antagonist 1.3 – 4.0 pKd 3x10-5 - 3x10-4 0.0 – -102.0 1
⤷ pKd 1.3 – 4.0 Conc range: 3x10-5 - 3x10-4 M [1]
Holding voltage: 0.0 – -102.0 mV
Channel Blocker Comments
The action of the majority of these molecules is voltage dependant [1-2,31]. Endogenous inhibitors are intracellular Mg2+ and polyamines (spermine4+, spermidine3+, putrescine2+).
Tissue Distribution Click here for help
Aortic endothelial cells.
Species:  Human
Technique:  Western blotting
References:  5
Forebrain, skeletal muscle, heart, macrophage cells.
Species:  Mouse
Technique:  Northern Blot
References:  10
Olfactory bulb, neocortex, hippocampus (dentate gyrus), basal ganglia (caudate putamen, nucleus accumbens, lateral olfactory tract nucleus), midbrain (superior colliculus, anterior pretectal nucleus, deep mesencephalic nucleus). motorneurons.
Species:  Rat
Technique:  In situ hybridisation
References:  9,21
Schwann cell microvilli
Species:  Rat
Technique:  Immunocytochemistry
References:  16
Tissue Distribution Comments
Expression in the thalamus has been reported by [21], but not by [9].
Physiological Functions Click here for help
Maintenance of a resting membrane potential.
Species:  None
Tissue: 
References: 
Repolarisation of cardiac action potential.
Species:  None
Tissue:  Heart.
References: 
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnj2tm1Swz Kcnj2tm1Swz/Kcnj2tm1Swz
involves: 129S1/Sv * 129X1/SvJ * FVB		 MGI:104744  MP:0000455 abnormal maxilla morphology PMID: 10904001 
Kcnj2tm1Swz Kcnj2tm1Swz/Kcnj2tm1Swz
involves: 129S1/Sv * 129X1/SvJ * FVB		 MGI:104744  MP:0001613 abnormal vasodilation PMID: 10904001 
Kcnj2tm1Swz Kcnj2tm1Swz/Kcnj2tm1Swz
involves: 129S1/Sv * 129X1/SvJ * FVB		 MGI:104744  MP:0009890 cleft secondary palate PMID: 10904001 
Kcnj2tm1Swz Kcnj2tm1Swz/Kcnj2tm1Swz
involves: 129S1/Sv * 129X1/SvJ * FVB		 MGI:104744  MP:0001575 cyanosis PMID: 10904001 
Kcnj2tm1Swz Kcnj2tm1Swz/Kcnj2tm1Swz
involves: 129S1/Sv * 129X1/SvJ * FVB		 MGI:104744  MP:0002058 neonatal lethality PMID: 10904001 
Kcnj2tm1Swz Kcnj2tm1Swz/Kcnj2tm1Swz
involves: 129S1/Sv * 129X1/SvJ * FVB		 MGI:104744  MP:0009888 palatal shelves fail to meet at midline PMID: 10904001 
Kcnj2tm1Swz Kcnj2tm1Swz/Kcnj2tm1Swz
involves: 129S1/Sv * 129X1/SvJ * FVB		 MGI:104744  MP:0001954 respiratory distress PMID: 10904001 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Andersen-Tawil syndrome
Synonyms: Andersen cardiodysrhythmic periodic paralysis [OMIM: 170390]
Andersen's syndrome
Andersen syndrome
Cardiodysrhythmic potassium-sensitive periodic paralysis [Orphanet: ORPHA37553]
Disease Ontology: DOID:0050434
OMIM: 170390
Orphanet: ORPHA37553
Role:  Disruption of the flow of potassium ions in skeletal and cardiac muscle.
Comments:  Characteristics of Andersen-Tawil syndrome are periodic paralysis, cardiac arrhythmia and developmental abnormalities.
References:  15,18
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
In-frame deletion Human 95_98del 513-524del 18
In-frame deletion Human 314_315del 1167-1172del 18
Missense Human D71V 18
Missense Human S136F 18
Missense Human G144S 18
Missense Human R218W/Q 18
Missense Human G300V 18
Missense Human V302M 15
Missense Human E303K 18
Disease:  Atrial fibrillation, familial, 9; ATFB9
Synonyms: Familial atrial fibrillation [Orphanet: ORPHA334] [Disease Ontology: DOID:0050650]
Disease Ontology: DOID:0050650
OMIM: 613980
Orphanet: ORPHA334
Disease:  Short QT syndrome-3; SQT3
Synonyms: Familial short QT syndrome [Orphanet: ORPHA51083]
OMIM: 609622
Orphanet: ORPHA51083
Role:  Increased Kir current in skeletal and cardiac ventricular muscle
Comments:  Characteristics of SQT3 are shortened QT interval leading to arrhythmia and potentially sudden death.
References:  6,20

References

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1. Abrams CJ, Davies NW, Shelton PA, Stanfield PR. (1996) The role of a single aspartate residue in ionic selectivity and block of a murine inward rectifier K+ channel Kir2.1. J Physiol (Lond.), 493 ( Pt 3): 643-9. [PMID:8799888]

2. Alagem N, Dvir M, Reuveny E. (2001) Mechanism of Ba(2+) block of a mouse inwardly rectifying K+ channel: differential contribution by two discrete residues. J Physiol (Lond.), 534 (Pt. 2): 381-93. [PMID:11454958]

3. Dart C, Leyland ML. (2001) Targeting of an A kinase-anchoring protein, AKAP79, to an inwardly rectifying potassium channel, Kir2.1. J Biol Chem, 276 (23): 20499-505. [PMID:11287423]

4. Fakler B, Bond CT, Adelman JP, Ruppersberg JP. (1996) Heterooligomeric assembly of inward-rectifier K+ channels from subunits of different subfamilies: Kir2.1 (IRK1) and Kir4.1 (BIR10). Pflugers Arch, 433 (1-2): 77-83. [PMID:9019734]

5. Fang Y, Schram G, Romanenko VG, Shi C, Conti L, Vandenberg CA, Davies PF, Nattel S, Levitan I. (2005) Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2. Am J Physiol, Cell Physiol, 289 (5): C1134-44. [PMID:15958527]

6. Hattori T, Makiyama T, Akao M, Ehara E, Ohno S, Iguchi M, Nishio Y, Sasaki K, Itoh H, Yokode M et al.. (2012) A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents. Cardiovasc Res, 93 (4): 666-73. [PMID:22155372]

7. Huang CL, Feng S, Hilgemann DW. (1998) Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature, 391 (6669): 803-6. [PMID:9486652]

8. Ishihara K, Hiraoka M, Ochi R. (1996) The tetravalent organic cation spermine causes the gating of the IRK1 channel expressed in murine fibroblast cells. J Physiol (Lond.), 491 ( Pt 2): 367-81. [PMID:8866861]

9. Karschin C, Dissmann E, Stühmer W, Karschin A. (1996) IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. J Neurosci, 16 (11): 3559-70. [PMID:8642402]

10. Kubo Y, Baldwin TJ, Jan YN, Jan LY. (1993) Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature, 362 (6416): 127-33. [PMID:7680768]

11. Leonoudakis D, Conti LR, Anderson S, Radeke CM, McGuire LM, Adams ME, Froehner SC, Yates 3rd JR, Vandenberg CA. (2004) Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)-associated proteins. J Biol Chem, 279 (21): 22331-46. [PMID:15024025]

12. Leonoudakis D, Conti LR, Radeke CM, McGuire LM, Vandenberg CA. (2004) A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels. J Biol Chem, 279 (18): 19051-63. [PMID:14960569]

13. Leonoudakis D, Mailliard W, Wingerd K, Clegg D, Vandenberg C. (2001) Inward rectifier potassium channel Kir2.2 is associated with synapse-associated protein SAP97. J Cell Sci, 114 (Pt 5): 987-98. [PMID:11181181]

14. Leyland ML, Dart C. (2004) An alternatively spliced isoform of PSD-93/chapsyn 110 binds to the inwardly rectifying potassium channel, Kir2.1. J Biol Chem, 279 (42): 43427-36. [PMID:15304517]

15. Ma D, Tang XD, Rogers TB, Welling PA. (2007) An andersen-Tawil syndrome mutation in Kir2.1 (V302M) alters the G-loop cytoplasmic K+ conduction pathway. J Biol Chem, 282 (8): 5781-9. [PMID:17166852]

16. Mi H, Deerinck TJ, Jones M, Ellisman MH, Schwarz TL. (1996) Inwardly rectifying K+ channels that may participate in K+ buffering are localized in microvilli of Schwann cells. J Neurosci, 16 (8): 2421-9. [PMID:8786419]

17. Nehring RB, Wischmeyer E, Döring F, Veh RW, Sheng M, Karschin A. (2000) Neuronal inwardly rectifying K(+) channels differentially couple to PDZ proteins of the PSD-95/SAP90 family. J Neurosci, 20 (1): 156-62. [PMID:10627592]

18. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R et al.. (2001) Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell, 105 (4): 511-9. [PMID:11371347]

19. Preisig-Müller R, Schlichthörl G, Goerge T, Heinen S, Brüggemann A, Rajan S, Derst C, Veh RW, Daut J. (2002) Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome. Proc Natl Acad Sci USA, 99 (11): 7774-9. [PMID:12032359]

20. Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S et al.. (2005) A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res, 96 (7): 800-7. [PMID:15761194]

21. Prüss H, Derst C, Lommel R, Veh RW. (2005) Differential distribution of individual subunits of strongly inwardly rectifying potassium channels (Kir2 family) in rat brain. Brain Res Mol Brain Res, 139 (1): 63-79. [PMID:15936845]

22. Raab-Graham KF, Radeke CM, Vandenberg CA. (1994) Molecular cloning and expression of a human heart inward rectifier potassium channel. Neuroreport, 5 (18): 2501-5. [PMID:7696590]

23. Rapedius M, Soom M, Shumilina E, Schulze D, Schönherr R, Kirsch C, Lang F, Tucker SJ, Baukrowitz T. (2005) Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. J Biol Chem, 280 (35): 30760-7. [PMID:15980413]

24. Sampson LJ, Leyland ML, Dart C. (2003) Direct interaction between the actin-binding protein filamin-A and the inwardly rectifying potassium channel, Kir2.1. J Biol Chem, 278 (43): 41988-97. [PMID:12923176]

25. Schram G, Melnyk P, Pourrier M, Wang Z, Nattel S. (2002) Kir2.4 and Kir2.1 K(+) channel subunits co-assemble: a potential new contributor to inward rectifier current heterogeneity. J Physiol (Lond.), 544 (2): 337-49. [PMID:12381809]

26. Shumilina E, Klöcker N, Korniychuk G, Rapedius M, Lang F, Baukrowitz T. (2006) Cytoplasmic accumulation of long-chain coenzyme A esters activates KATP and inhibits Kir2.1 channels. J Physiol (Lond.), 575 (Pt 2): 433-42. [PMID:16777940]

27. Soom M, Schönherr R, Kubo Y, Kirsch C, Klinger R, Heinemann SH. (2001) Multiple PIP2 binding sites in Kir2.1 inwardly rectifying potassium channels. FEBS Lett, 490 (1-2): 49-53. [PMID:11172809]

28. Wischmeyer E, Döring F, Karschin A. (1998) Acute suppression of inwardly rectifying Kir2.1 channels by direct tyrosine kinase phosphorylation. J Biol Chem, 273 (51): 34063-8. [PMID:9852063]

29. Wischmeyer E, Karschin A. (1996) Receptor stimulation causes slow inhibition of IRK1 inwardly rectifying K+ channels by direct protein kinase A-mediated phosphorylation. Proc Natl Acad Sci USA, 93 (12): 5819-23. [PMID:8650176]

30. Wischmeyer E, Lentes KU, Karschin A. (1995) Physiological and molecular characterization of an IRK-type inward rectifier K+ channel in a tumour mast cell line. Pflugers Arch, 429 (6): 809-19. [PMID:7603835]

31. Yang J, Jan YN, Jan LY. (1995) Control of rectification and permeation by residues in two distinct domains in an inward rectifier K+ channel. Neuron, 14 (5): 1047-54. [PMID:7748552]

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