Kir6.2

Target id: 442

Nomenclature: Kir6.2

Family: Inwardly rectifying potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 0 390 11p15.1 KCNJ11 potassium inwardly-rectifying channel, subfamily J, member 11 4
Mouse 2 0 390 7 B3 Kcnj11 potassium inwardly rectifying channel, subfamily J, member 11 4,14
Rat 2 0 390 1q22 Kcnj11 potassium inwardly rectifying channel, subfamily J, member 11 6
Previous and Unofficial Names
BIR
ATP-sensitive inward rectifier potassium channel 11
inward rectifier K(+) channel Kir6.2
KATP
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
SUR2B 6
SUR2A 5
ATP-binding cassette, sub-family C (CFTR/MRP), member 8 4
Other Associated Proteins
Name References
Not determined
Associated Protein Comments
Kir6.2 forms IK.ATP when in complex with SUR1 in pancreatic β cells [1,4], SUR2A in heart and skeletal muscle [5] and SUR2B in smooth muscle [6].
Functional Characteristics
ATP-sensitive, inward-rectifier current
Ion Selectivity and Conductance
Species:  Mouse
Rank order:  K+
References:  2,4-5
Ion Selectivity and Conductance Comments
Conductance has been measured in heteromers of Kir6.2 coexpressed with either SUR1 (74.3-76.4pS, [2,4]) or SUR2A (79.3pS, [5]).
Associated subunits (Human)
SUR1, SUR2A, SUR2B
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
diazoxide Rn Agonist - - 2x10-4 -60.0 6
Conc range: 2x10-4 M [6]
Holding voltage: -60.0 mV
pinacidil Rn Agonist - - 1x10-4 -60.0 6
Conc range: 1x10-4 M [6]
Holding voltage: -60.0 mV
pinacidil Mm Agonist - - 3x10-5 - 1x10-4 -60.0 5
Conc range: 3x10-5 - 1x10-4 M [5]
Holding voltage: -60.0 mV
cromakalim Mm Agonist - - 3x10-5 -60.0 5
Conc range: 3x10-5 M [5]
Holding voltage: -60.0 mV
diazoxide Mm Agonist 4.2 pEC50 - Physiological 4
pEC50 4.2 (EC50 6.3x10-5 M) [4]
Holding voltage: Physiological
nicorandil Hs - - - - -
minoxidil Hs - - - - -
View species-specific activator tables
Activator Comments
These studies were of Kir6.2 coexpressed with a member of the sulfonylurea receptor family (SUR1 [4], SUR2A [5] or SUR2B [6]).
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
glibenclamide Hs - - - - -
Gating inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
ATP Mm Antagonist - - - -60.0 4-5
[4-5]
Holding voltage: -60.0 mV
Gating Inhibitor Comments
The pIC50 for Kir6.2 coexpressed with SUR1 and SUR2A are 5.0 and 4.0 respectively [4-5].
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
tolbutamide Rn Antagonist - - 5x10-4 -60.0 6
Conc range: 5x10-4 M [6]
Holding voltage: -60.0 mV
glibenclamide Rn Antagonist - - 1x10-6 -60.0 6
Conc range: 1x10-6 M [6]
Holding voltage: -60.0 mV
glibenclamide Mm Antagonist 5.7 pIC50 1x10-6 Physiological/ -60.0 4-5
pIC50 5.7 Conc range: 1x10-6 M [4-5]
Holding voltage: Physiological / -60.0 mV
tolbutamide Mm Antagonist 4.5 pIC50 - Physiological 4
pIC50 4.5 [4]
Holding voltage: Physiological
View species-specific channel blocker tables
Channel Blocker Comments
These studies were of Kir6.2 coexpressed with a member of the sulfonylurea receptor family (SUR1 [4], SUR2A [5] or SUR2B [6]).
Tissue Distribution
Skeletal muscle, heart, pancreatic islets, brain.
Species:  Rat
Technique:  Northern Blot
References:  4
Functional Assays
Single channel recording in cell-attached inside-out configurations of Kir6.2 coexpressed with either SUR1, SUR2A or SUR2B.
Species:  None
Tissue:  COS and HEK cells.
Response measured:  Current
References:  4-6
Physiological Functions
Regulation of insulin secretion.
Species:  Mouse
Tissue:  Pancreas
References:  10-11
Regulation of glucagon secretion.
Species:  Mouse
Tissue:  Hypothalamus
References:  8
Protection against cardiac damage by ischemic preconditioning.
Species:  Mouse
Tissue:  Heart
References:  15
Protection against stress-induced cardiac dysfunction.
Species:  Mouse
Tissue:  Heart
References:  17
Protection against hypoxia-induced generalised seizure.
Species:  Mouse
Tissue:  Substantia nigra
References:  16
Protection against degeneration of dopaminergic neurons.
Species:  Mouse
Tissue:  Sustantia nigra
References:  7
Physiological Consequences of Altering Gene Expression
Absence of Kir6.2 expression leads to glucose homeostasis (decreased insulin and glucagon secretion).
Species:  Mouse
Tissue:  Pancreatic β cells, hypothalamic glucose-responsive neurons.
Technique:  Knockout
References:  10
Absence of Kir6.2 expression leads to increased susceptibility to seizure propagation during metabolic stress and also protection against degeneration of dopaminergic neurons.
Species:  Mouse
Tissue:  Substantia nigra
Technique:  Knockout
References:  7,16
Absence of Kir6.2 expression leads to decreased ability to adapt to stress.
Species:  Mouse
Tissue:  Heart
Technique:  Knockout
References:  15,17
Decreased functional Kir6.2-containing channels lead to disregulated insulin secretion and decreased survival of β cell populations.
Species:  Mouse
Tissue:  Pancreatic β cells
Technique:  Dominant negative protein expression (Kir6.2 G132S)
References:  11
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnj11tm1Sse Kcnj11tm1Sse/Kcnj11tm1Sse
B6.129-Kcnj11
MGI:107501  MP:0005402 abnormal action potential PMID: 15949470 
Kcnj11tm1Sse Kcnj11tm1Sse/Kcnj11tm1Sse
involves: 129P2/OlaHsd
MGI:107501  MP:0002727 decreased circulating insulin level PMID: 9724715 
Kcnj11Y12stop Kcnj11Y12stop/Kcnj11Y12stop
involves: BALB/c * C3H/HeH
MGI:107501  MP:0002711 decreased glucagon secretion PMID: 17503968 
Kcnj11tm1Sse Kcnj11tm1Sse/Kcnj11tm1Sse
involves: 129P2/OlaHsd
MGI:107501  MP:0005293 impaired glucose tolerance PMID: 9724715 
Kcnj11tm1Sse Kcnj11tm1Sse/Kcnj11tm1Sse
B6.129-Kcnj11
MGI:107501  MP:0005522 increased circulating atrial natriuretic factor PMID: 15949470 
Kcnj11Y12stop Kcnj11Y12stop/Kcnj11Y12stop
involves: BALB/c * C3H/HeH
MGI:107501  MP:0003058 increased insulin secretion PMID: 17503968 
Kcnj11tm1Sse Kcnj11tm1Sse/Kcnj11tm1Sse
involves: 129P2/OlaHsd
MGI:107501  MP:0002891 increased insulin sensitivity PMID: 9724715 
Kcnj11tm1Sse Kcnj11tm1Sse/Kcnj11tm1Sse
B6.129-Kcnj11
MGI:107501  MP:0004875 increased mean systemic arterial blood pressure PMID: 15949470 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
Orphanet:  276580
Disease:  Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
Orphanet:  79644
Disease:  Diabetes mellitus, transient neonatal, 3
OMIM:  610582
Orphanet:  99886
Disease:  Diabetes mellitus, type 2, susceptibility to
OMIM:  125853
Orphanet:  552
Disease:  Hyperinsulinemic hypoglycemia, familial, 2
OMIM:  601820
Orphanet:  276603
Disease:  Permanent neonatal diabetes mellitus (PNDM)
OMIM:  606176
Orphanet:  79134, 99885
Role: 
Drugs: 
Side effects:  Diarrhoea during transfer from insulin to sulfonylurea treatment.
Therapeutic use:  PNDM due to most KCNJ11 mutations.
References:  3,12-13
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human F35V 13
Missense Human H46Y 13
Missense Human R50Q 13
Missense Human Q52R 3,13
Missense Human G53R 13
Missense Human G53N 13
Missense Human V59G 3
Missense Human V59M 3,13
Missense Human L164P 13
Missense Human K170T 13
Missense Human R201C 3,13
Missense Human R201H 3
Missense Human R201L 13
Missense Human I296L 3,13
Missense Human E322K 13
Missense Human Y330S 13
Missense Human F333I 13
Disease:  Persistent hyperinsulinemiac hypoglycemia in infancy (PHHI)
OMIM:  601820
References:  12
Click column headers to sort
Type Species Molecular location Description Reference
Truncation Human Y12X 12
General Comments
The sulfonyurea drugs (acetohexamide, tolbutamide and glibenclamide) inhibit sufonylurea receptors. The functional sulfonylurea receptor has been characterised as a hetero-octamer formed by four SUR (ATP binding cassette transporter, ABCC8 or ABCC9) and four Kir6.2 (inwardly rectifying potassium channel) subunits, with the Kir6.2 subunits forming the core ion pore and the SUR subunits providing the regulatory properties [9]. Co-expression of Kir6.2 with SUR1, reconstitutes the ATP-dependent K+ conductivity inhibited by the sulfonyureas [4].

References

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1. Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP, Boyd AE, González G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA. (1995) Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science268 (5209): 423-6. [PMID:7716547]

2. Béguin P, Nagashima K, Nishimura M, Gonoi T, Seino S. (1999) PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. EMBO J.18 (17): 4722-32. [PMID:10469651]

3. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT. (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med.350 (18): 1838-49. [PMID:15115830]

4. Inagaki N, Gonoi T, Clement JP, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science270 (5239): 1166-70. [PMID:7502040]

5. Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, Seino S. (1996) A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron16 (5): 1011-7. [PMID:8630239]

6. Isomoto S, Kondo C, Yamada M, Matsumoto S, Higashiguchi O, Horio Y, Matsuzawa Y, Kurachi Y. (1996) A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. J. Biol. Chem.271 (40): 24321-4. [PMID:8798681]

7. Liss B, Haeckel O, Wildmann J, Miki T, Seino S, Roeper J. (2005) K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat. Neurosci.8 (12): 1742-51. [PMID:16299504]

8. Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y, Horiuchi M, Ashcroft F, Minokoshi Y, Roeper J, Seino S. (2001) ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat. Neurosci.4 (5): 507-12. [PMID:11319559]

9. Miki T, Nagashima K, Seino S. (1999) The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells. J. Mol. Endocrinol.22 (2): 113-23. [PMID:10194514]

10. Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A, Gonoi T, Iwanaga T, Miyazaki J, Seino S. (1998) Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc. Natl. Acad. Sci. U.S.A.95 (18): 10402-6. [PMID:9724715]

11. Miki T, Tashiro F, Iwanaga T, Nagashima K, Yoshitomi H, Aihara H, Nitta Y, Gonoi T, Inagaki N, Miyazaki J, Seino S. (1997) Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. Proc. Natl. Acad. Sci. U.S.A.94 (22): 11969-73. [PMID:9342346]

12. Nestorowicz A, Inagaki N, Gonoi T, Schoor KP, Wilson BA, Glaser B, Landau H, Stanley CA, Thornton PS, Seino S, Permutt MA. (1997) A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes46 (11): 1743-8. [PMID:9356020]

13. Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Søvik O, Polak M, Hattersley AT. (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N. Engl. J. Med.355 (5): 467-77. [PMID:16885550]

14. Sakura H, Bond C, Warren-Perry M, Horsley S, Kearney L, Tucker S, Adelman J, Turner R, Ashcroft FM. (1995) Characterization and variation of a human inwardly-rectifying-K-channel gene (KCNJ6): a putative ATP-sensitive K-channel subunit. FEBS Lett.367 (2): 193-7. [PMID:7796919]

15. Suzuki M, Sasaki N, Miki T, Sakamoto N, Ohmoto-Sekine Y, Tamagawa M, Seino S, Marbán E, Nakaya H. (2002) Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. J. Clin. Invest.109 (4): 509-16. [PMID:11854323]

16. Yamada K, Ji JJ, Yuan H, Miki T, Sato S, Horimoto N, Shimizu T, Seino S, Inagaki N. (2001) Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science292 (5521): 1543-6. [PMID:11375491]

17. Zingman LV, Hodgson DM, Bast PH, Kane GC, Perez-Terzic C, Gumina RJ, Pucar D, Bienengraeber M, Dzeja PP, Miki T, Seino S, Alekseev AE, Terzic A. (2002) Kir6.2 is required for adaptation to stress. Proc. Natl. Acad. Sci. U.S.A.99 (20): 13278-83. [PMID:12271142]

How to cite this page

Paul A. Slesinger, Colin G. Nichols, Stephen Tucker, Lawrence G. Palmer, Henry Sackin, John P. Adelman, David E. Clapham, Hiroshi Hibino, Atsushi Inanobe, Lily Y. Jan, Andreas Karschin, Yoshihiro Kubo, Yoshihisa Kurachi, Michel Lazdunski, Takashi Miki, Wade L. Pearson, Susumu Seino, Carol A. Vandenberg.
Inwardly rectifying potassium channels: Kir6.2. Last modified on 23/10/2014. Accessed on 25/11/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=442.