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Kir6.2

Family: Inwardly rectifying potassium channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Activators
Gating Inhibitors
Pore Blockers
Tissue Distribution
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
References
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 4,13
Rat 2 0 390 1q22 Kcnj11 potassium inwardly rectifying channel, subfamily J, member 11 6
Previous and Unofficial Names
Kir6.2
βIR
KATP-β
BIR
ATP-sensitive inward rectifier potassium channel 11
inward rectifier K(+) channel Kir6.2
potassium channel, inwardly rectifying subfamily J member 11
potassium inwardly-rectifying channel subfamily J member 11
AI842722
AW491124
Database Links
ChEMBL Target 285 (Hs), 100584 (Mm), 100109 (Rn)
DrugBank Target 781 (Hs)
Ensembl ENSG00000187486 (Hs), ENSMUSG00000070561 (Mm), ENSRNOG00000021128 (Rn)
Entrez Gene 3767 (Hs), 16514 (Mm), 83535 (Rn)
GeneCards KCNJ11 (Hs)
GenitoUrinary Development Molecular Anatomy Project Kcnj11 (Mm)
HomoloGene 441 (Hs)
Human Protein Reference Database 09022 (Hs)
InterPro Q14654 (Hs), Q61743 (Mm), P70673 (Rn)
KEGG Gene hsa:3767 (Hs), mmu:16514 (Mm), rno:83535 (Rn)
OMIM 600937 (Hs)
Orphanet Gene ORPHA122787 (Hs)
PharmGKB Gene PA217 (Hs)
PhosphoSitePlus Q14654 (Hs), Q61743 (Mm)
Protein Ontology (PRO) PRO:000001980 (Hs)
RefSeq Nucleotide NM_000525 (Hs), NM_010602 (Mm), NM_031358 (Rn)
RefSeq Protein NP_000516 (Hs), NP_034732 (Mm), NP_112648 (Rn)
TreeFam ENSG00000187486 (Hs), ENSMUSG00000070561 (Mm), ENSRNOG00000021128 (Rn)
UniGene Hs. 248141 (Hs)
UniProt Q14654 (Hs), Q61743 (Mm), P70673 (Rn)
Wikipedia Kir6.2
Potassium channels
Search for 3D structures on the PDB
Search by keyword: Inwardly rectifying potassium channels Kir6.2 Search by accession number: Q14654, P70673, Q61743
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
SUR2B 6
SUR2A 5
SUR1 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].
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. Affinity Units Concentration range (M) Holding voltage (mV) Reference
diazoxide Rn - - 2x10-4 -60.0 6
pinacidil Rn - - 1x10-4 -60.0 6
pinacidil Mm - - 3x10-5 - 1x10-4 -60.0 5
cromakalim Mm - - 3x10-5 -60.0 5
diazoxide Mm 4.2 pEC50 - Physiological 4
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]).
Gating inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
ATP Mm - - - -60.0 4-5
Gating Inhibitor Comments
The pIC50 for Kir6.2 coexpressed with SUR1 and SUR2A are 5.0 and 4.0 respectively [4-5].
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
tolbutamide Rn - - 5x10-4 -60.0 6
glibenclamide Rn - - 1x10-6 -60.0 6
glibenclamide Mm 5.7 pIC50 1x10-6 Physiological 4-5
tolbutamide Mm 4.5 pIC50 - Physiological 4
View species-specific pore blocker tables
Pore 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:  9-10
Regulation of glucagon secretion.
Species:  Mouse
Tissue:  Hypothalamus
References:  8
Protection against cardiac damage by ischemic preconditioning.
Species:  Mouse
Tissue:  Heart
References:  14
Protection against stress-induced cardiac dysfunction.
Species:  Mouse
Tissue:  Heart
References:  16
Protection against hypoxia-induced generalised seizure.
Species:  Mouse
Tissue:  Substantia nigra
References:  15
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 increased susceptibility to seizure propagation during metabolic stress and also protection against degeneration of dopaminergic neurons.
Species:  Mouse
Tissue:  Substantia nigra
Technique:  Knockout
References:  7,15
Absence of Kir6.2 expression leads to decreased ability to adapt to stress.
Species:  Mouse
Tissue:  Heart
Technique:  Knockout
References:  14,16
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:  9
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:  10
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

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:  Persistent hyperinsulinemiac hypoglycemia in infancy (PHHI).
OMIM:  601820
References:  11
Click column headers to sort
Type Species Molecular location Description Reference
Truncation Human Y12X 11
Disease:  Permanent neonatal diabetes mellitus (PNDM).
OMIM:  606176
Orphanet:  79134, 99885
Role:  Disregulation of insulin secretion by pancreatic β cells due to decreased sensitivity of KATP channels to ATP inhibiton.
Drugs:  Sulfonylureas, particularly glibenclamide.
Side effects:  Diarrhoea during transfer from insulin to sulfonylurea treatment.
Therapeutic use:  PNDM due to most KCNJ11 mutations.
References:  3,11-12
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human F333I 12
Missense Human Y330S 12
Missense Human E322K 12
Missense Human I296L 3,12
Missense Human R201L 12
Missense Human R201H 3
Missense Human R201C 3,12
Missense Human K170T 12
Missense Human L164P 12
Missense Human V59M 3,12
Missense Human V59G 3
Missense Human G53R 12
Missense Human G53N 12
Missense Human Q52R 3,12
Missense Human R50Q 12
Missense Human H46Y 12
Missense Human F35V 12
Disease:  Diabetes mellitus, transient neonatal, 3
OMIM:  610582
Orphanet:  99886
References: 
Mutations not determined

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. Science, 268 (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. Science, 270 (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. Neuron, 16 (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; 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]

10. 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]

11. 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. Diabetes, 46 (11): 1743-8. [PMID:9356020]

12. 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]

13. 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]

14. 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]

15. 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. Science, 292 (5521): 1543-6. [PMID:11375491]

16. 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]

To cite this database page, please use the following:

John P. Adelman, David E. Clapham, Hiroshi Hibino, Atsushi Inanobe, Lily Y. Jan, Andreas Karschin, Yoshihiro Kubo, Yoshihisa Kurachi, Michel Lazdunski, Takashi Miki, Colin G. Nichols, Wade L. Pearson, Susumu Seino, Carol A. Vandenberg.
Inwardly rectifying potassium channels: Kir6.2. Last modified on 20/01/2012. Accessed on 23/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=442.


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