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Kir6.2

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Target id: 442

Nomenclature: Kir6.2

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 0 390 11p15.1 KCNJ11 potassium inwardly rectifying channel subfamily J member 11 4
Mouse 2 0 390 7 29.66 cM Kcnj11 potassium inwardly rectifying channel, subfamily J, member 11 4,15
Rat 2 0 390 1q22 Kcnj11 potassium inwardly-rectifying channel, subfamily J, member 11 6
Previous and Unofficial Names Click here for help
potassium inwardly-rectifying channel | potassium inwardly rectifying channel subfamily J member 11 | ATP-sensitive inward rectifier potassium channel 11 | BIR | inward rectifier K(+) channel Kir6.2 | KATP-β | potassium channel, inwardly rectifying subfamily J, member 11 | potassium inwardly rectifying channel | potassium inwardly rectifying channel, subfamily J, member 11 | potassium inwardly-rectifying channel, subfamily J, member 11 | potassium voltage-gated channel subfamily J member 11
Database Links Click here for help
Alphafold Q14654 (Hs), Q61743 (Mm), P70673 (Rn)
CATH/Gene3D 2.60.40.1400
ChEMBL Target CHEMBL1886 (Hs), CHEMBL3038487 (Rn)
DrugBank Target Q14654 (Hs)
Ensembl Gene ENSG00000187486 (Hs), ENSMUSG00000096146 (Mm), ENSRNOG00000021128 (Rn)
Entrez Gene 3767 (Hs), 16514 (Mm), 83535 (Rn)
Human Protein Atlas ENSG00000187486 (Hs)
KEGG Gene hsa:3767 (Hs), mmu:16514 (Mm), rno:83535 (Rn)
OMIM 600937 (Hs)
Orphanet ORPHA122787 (Hs)
Pharos Q14654 (Hs)
RefSeq Nucleotide NM_000525 (Hs), NM_010602 (Mm), NM_031358 (Rn)
RefSeq Protein NP_000516 (Hs), NP_034732 (Mm), NP_112648 (Rn)
UniProtKB Q14654 (Hs), Q61743 (Mm), P70673 (Rn)
Wikipedia KCNJ11 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of a Pancreatic ATP-Sensitive Potassium Channel
PDB Id:  5WUA
Ligand:  glibenclamide
Resolution:  5.6Å
Species:  Mouse
References:  7
Associated Proteins Click here for help
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 Click here for help
ATP-sensitive, inward-rectifier current
Ion Selectivity and Conductance Click here for help
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

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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
diazoxide Small molecule or natural product Approved drug Ligand has a PDB structure Rn Agonist - - 2x10-4 -60.0 6
⤷ Conc range: 2x10-4 M [6]
Holding voltage: -60.0 mV
pinacidil Small molecule or natural product Approved drug Rn Agonist - - 1x10-4 -60.0 6
⤷ Conc range: 1x10-4 M [6]
Holding voltage: -60.0 mV
pinacidil Small molecule or natural product Approved drug Click here for species-specific activity table Mm Agonist - - 3x10-5 - 1x10-4 -60.0 5
⤷ Conc range: 3x10-5 - 1x10-4 M [5]
Holding voltage: -60.0 mV
cromakalim Small molecule or natural product Click here for species-specific activity table Mm Agonist - - 3x10-5 -60.0 5
⤷ Conc range: 3x10-5 M [5]
Holding voltage: -60.0 mV
diazoxide Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Agonist 4.2 pEC50 - Physiological 4
⤷ pEC50 4.2 (EC50 6.3x10-5 M) [4]
Holding voltage: Physiological
nicorandil Small molecule or natural product Approved drug Hs - - - - -
⤷
minoxidil Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure 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 Value Parameter Concentration range (M) Holding voltage (mV) Reference
glibenclamide Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs - - - - -
⤷
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
ATP Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure 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 Value Parameter Concentration range (M) Holding voltage (mV) Reference
tolbutamide Small molecule or natural product Approved drug Rn Antagonist - - 5x10-4 -60.0 6
⤷ Conc range: 5x10-4 M [6]
Holding voltage: -60.0 mV
glibenclamide Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Rn Antagonist - - 1x10-6 -60.0 6
⤷ Conc range: 1x10-6 M [6]
Holding voltage: -60.0 mV
glibenclamide Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand 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 Small molecule or natural product Approved drug 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]).
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
Tissue Distribution Click here for help
Skeletal muscle, heart, pancreatic islets, brain.
Species:  Rat
Technique:  Northern Blot
References:  4
Functional Assays Click here for help
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 Click here for help
Regulation of insulin secretion.
Species:  Mouse
Tissue:  Pancreas
References:  11-12
Regulation of glucagon secretion.
Species:  Mouse
Tissue:  Hypothalamus
References:  9
Protection against cardiac damage by ischemic preconditioning.
Species:  Mouse
Tissue:  Heart
References:  16
Protection against stress-induced cardiac dysfunction.
Species:  Mouse
Tissue:  Heart
References:  18
Protection against hypoxia-induced generalised seizure.
Species:  Mouse
Tissue:  Substantia nigra
References:  17
Protection against degeneration of dopaminergic neurons.
Species:  Mouse
Tissue:  Sustantia nigra
References:  8
Physiological Consequences of Altering Gene Expression Click here for help
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:  8,17
Absence of Kir6.2 expression leads to decreased ability to adapt to stress.
Species:  Mouse
Tissue:  Heart
Technique:  Knockout
References:  16,18
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:  11
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:  12
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
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 Click here for help
Disease:  Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
Orphanet: ORPHA276580
Disease:  Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
Orphanet: ORPHA79644
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
Disease:  Diabetes mellitus, permanent neonatal; PNDM
Synonyms: DEND syndrome [Orphanet: ORPHA79134]
Developmental delay-epilepsy-neonatal diabetes syndrome [Orphanet: ORPHA79134]
Permanent neonatal diabetes mellitus [Orphanet: ORPHA99885]
OMIM: 606176
Orphanet: ORPHA99885, ORPHA79134
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:  3,13-14
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human F35V 14
Missense Human H46Y 14
Missense Human R50Q 14
Missense Human Q52R 3,14
Missense Human G53R 14
Missense Human G53N 14
Missense Human V59G 3
Missense Human V59M 3,14
Missense Human L164P 14
Missense Human K170T 14
Missense Human R201C 3,14
Missense Human R201H 3
Missense Human R201L 14
Missense Human I296L 3,14
Missense Human E322K 14
Missense Human Y330S 14
Missense Human F333I 14
Disease:  Diabetes mellitus, transient neonatal, 3
Synonyms: Transient neonatal diabetes mellitus [Orphanet: ORPHA99886]
OMIM: 610582
Orphanet: ORPHA99886
Disease:  Hyperinsulinemic hypoglycemia, familial, 2; HHF2
Synonyms: Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency [Orphanet: ORPHA276603]
Hyperinsulinemic hypoglycemia [Disease Ontology: DOID:13317]
Persistent hyperinsulinemic hypoglycemia of infancy [OMIM: 601820]
Disease Ontology: DOID:13317
OMIM: 601820
Orphanet: ORPHA276603
References:  13
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Nonsense Human Y12X 13
Disease:  Maturity-onset diabetes of the young; MODY
Disease Ontology: DOID:0050524
OMIM: 606391
Orphanet: ORPHA552
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 [10]. 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 4th JP, Boyd 3rd 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 et al.. (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 4th 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. Li N, Wu JX, Ding D, Cheng J, Gao N, Chen L. (2017) Structure of a Pancreatic ATP-Sensitive Potassium Channel. Cell, 168 (1-2): 101-110.e10. [PMID:28086082]

8. 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]

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

10. 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]

11. 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 USA, 95 (18): 10402-6. [PMID:9724715]

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

13. Nestorowicz A, Inagaki N, Gonoi T, Schoor KP, Wilson BA, Glaser B, Landau H, Stanley CA, Thornton PS, Seino S et al.. (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]

14. Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V et al.. (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]

15. 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]

16. 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]

17. 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]

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

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