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Gene Review

KCNJ11  -  potassium channel, inwardly rectifying...

Homo sapiens

Synonyms: ATP-sensitive inward rectifier potassium channel 11, BIR, HHF2, IKATP, Inward rectifier K(+) channel Kir6.2, ...
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Disease relevance of KCNJ11


High impact information on KCNJ11

  • The N-terminal domain consists of transactivation, CARD, Pyrin, or BIR domains, with a minority containing undefined domains [6].
  • Mutations in both the SUR1 and KIR6.2 genes have been shown to cause familial hyperinsulinism, indicating the importance of the pancreatic beta-cell channel in the regulation of insulin secretion [7].
  • Potassium currents in the myocardium can be classified into one of two general categories: 1) inward rectifying currents such as IK1, IKACh, and IKATP; and 2) primarily voltage-gated currents such as IKs, IKr, IKp, IKur, and Ito [8].
  • We show here that the primary site at which ATP acts to mediate K-ATP channel inhibition is located on Kir6.2, and that SUR1 is required for sensitivity to sulphonylureas and diazoxide and for activation by Mg-ADP [9].
  • The four open reading frames (ORFs) possess three baculoviral inhibition of apoptosis protein repeat (BIR) domains and a carboxy-terminal RING zinc-finger [10].

Chemical compound and disease context of KCNJ11


Biological context of KCNJ11

  • The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro [16].
  • Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes [17].
  • RESULTS: The EE, EK and KK genotype frequencies of the KCNJ11 E23K polymorphism differed significantly between GDM and control women (31.5, 52.7 and 15.8% vs 37.3, 48.8 and 13.9%, respectively; p=0.050) [3].
  • We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11 [18].
  • Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened [18].

Anatomical context of KCNJ11


Associations of KCNJ11 with chemical compounds


Physical interactions of KCNJ11

  • Only SUR1 and SUR1Delta17 showed high-affinity binding of glibenclamide (K(d) approximately 2 nM in the presence of 1 mM ATP) and formed functional K(ATP) channels upon coexpression with Kir6.2 [29].
  • However, until now the existence of such heteromultimeric Kir6.1/Kir6.2 complexes has not been demonstrated for native K(ATP) channels [30].

Enzymatic interactions of KCNJ11


Regulatory relationships of KCNJ11

  • (86)Rb(+) efflux and electrophysiological studies of R1353H SUR1 coexpressed with wild-type Kir6.2 in COSm6 cells demonstrated partially impaired ATP-dependent potassium channel function [32].

Other interactions of KCNJ11

  • In conclusion, our results showed no evidence of a synergistic interaction between the KCNJ11 Glu(23)Lys and PPARG Pro(12)Ala polymorphisms, but indicated that they may act in an additive manner to increase the risk of type 2 diabetes [33].
  • We are the first to show that K(ATP) channel in human corporal smooth muscle is composed of Kir6.1-Kir6.2 construct expressed with SUR2B by RT-PCR [34].
  • We investigated whether mutations in KCNJ11 could also give rise to TNDM [16].
  • Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations [35].
  • In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy [16].

Analytical, diagnostic and therapeutic context of KCNJ11


  1. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Bitner-Glindzicz, M., Lindley, K.J., Rutland, P., Blaydon, D., Smith, V.V., Milla, P.J., Hussain, K., Furth-Lavi, J., Cosgrove, K.E., Shepherd, R.M., Barnes, P.D., O'Brien, R.E., Farndon, P.A., Sowden, J., Liu, X.Z., Scanlan, M.J., Malcolm, S., Dunne, M.J., Aynsley-Green, A., Glaser, B. Nat. Genet. (2000) [Pubmed]
  2. A novel KCNJ11 mutation associated with congenital hyperinsulinism reduces the intrinsic open probability of beta-cell ATP-sensitive potassium channels. Lin, Y.W., MacMullen, C., Ganguly, A., Stanley, C.A., Shyng, S.L. J. Biol. Chem. (2006) [Pubmed]
  3. Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus. Shaat, N., Ekelund, M., Lernmark, A., Ivarsson, S., Almgren, P., Berntorp, K., Groop, L. Diabetologia (2005) [Pubmed]
  4. KCNJ11 polymorphisms and sudden cardiac death in patients with acute myocardial infarction. Jeron, A., Hengstenberg, C., Holmer, S., Wollnik, B., Riegger, G.A., Schunkert, H., Erdmann, J. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  5. ABCC8 and ABCC9: ABC transporters that regulate K(+) channels. Bryan, J., Muñoz, A., Zhang, X., Düfer, M., Drews, G., Krippeit-Drews, P., Aguilar-Bryan, L. Pflugers Arch. (2007) [Pubmed]
  6. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Ting, J.P., Davis, B.K. Annu. Rev. Immunol. (2005) [Pubmed]
  7. Toward understanding the assembly and structure of KATP channels. Aguilar-Bryan, L., Clement, J.P., Gonzalez, G., Kunjilwar, K., Babenko, A., Bryan, J. Physiol. Rev. (1998) [Pubmed]
  8. Molecular physiology of cardiac potassium channels. Deal, K.K., England, S.K., Tamkun, M.M. Physiol. Rev. (1996) [Pubmed]
  9. Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Tucker, S.J., Gribble, F.M., Zhao, C., Trapp, S., Ashcroft, F.M. Nature (1997) [Pubmed]
  10. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Liston, P., Roy, N., Tamai, K., Lefebvre, C., Baird, S., Cherton-Horvat, G., Farahani, R., McLean, M., Ikeda, J.E., MacKenzie, A., Korneluk, R.G. Nature (1996) [Pubmed]
  11. Hyperinsulinism in mice with heterozygous loss of K(ATP) channels. Remedi, M.S., Rocheleau, J.V., Tong, A., Patton, B.L., McDaniel, M.L., Piston, D.W., Koster, J.C., Nichols, C.G. Diabetologia (2006) [Pubmed]
  12. Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives. Hansen, J.B. Current medicinal chemistry. (2006) [Pubmed]
  13. Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function. Marthinet, E., Bloc, A., Oka, Y., Tanizawa, Y., Wehrle-Haller, B., Bancila, V., Dubuis, J.M., Philippe, J., Schwitzgebel, V.M. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  14. Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. Zung, A., Glaser, B., Nimri, R., Zadik, Z. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  15. Predominant Th1 cell infiltration in acute rejection episodes of human kidney grafts. D'Elios, M.M., Josien, R., Manghetti, M., Amedei, A., de Carli, M., Cuturi, M.C., Blancho, G., Buzelin, F., del Prete, G., Soulillou, J.P. Kidney Int. (1997) [Pubmed]
  16. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Gloyn, A.L., Reimann, F., Girard, C., Edghill, E.L., Proks, P., Pearson, E.R., Temple, I.K., Mackay, D.J., Shield, J.P., Freedenberg, D., Noyes, K., Ellard, S., Ashcroft, F.M., Gribble, F.M., Hattersley, A.T. Hum. Mol. Genet. (2005) [Pubmed]
  17. Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes. Eftychi, C., Howson, J.M., Barratt, B.J., Vella, A., Payne, F., Smyth, D.J., Twells, R.C., Walker, N.M., Rance, H.E., Tuomilehto-Wolf, E., Tuomilehto, J., Undlien, D.E., Rønningen, K.S., Guja, C., Ionescu-Tîirgovişte, C., Savage, D.A., Todd, J.A. Diabetes (2004) [Pubmed]
  18. Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. Tornovsky, S., Crane, A., Cosgrove, K.E., Hussain, K., Lavie, J., Heyman, M., Nesher, Y., Kuchinski, N., Ben-Shushan, E., Shatz, O., Nahari, E., Potikha, T., Zangen, D., Tenenbaum-Rakover, Y., de Vries, L., Argente, J., Gracia, R., Landau, H., Eliakim, A., Lindley, K., Dunne, M.J., Aguilar-Bryan, L., Glaser, B. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  19. Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Proks, P., Girard, C., Ashcroft, F.M. Hum. Mol. Genet. (2005) [Pubmed]
  20. Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Suchi, M., MacMullen, C.M., Thornton, P.S., Adzick, N.S., Ganguly, A., Ruchelli, E.D., Stanley, C.A. Mod. Pathol. (2006) [Pubmed]
  21. Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Suchi, M., MacMullen, C., Thornton, P.S., Ganguly, A., Stanley, C.A., Ruchelli, E.D. Pediatr. Dev. Pathol. (2003) [Pubmed]
  22. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Inagaki, N., Gonoi, T., Clement, J.P., Namba, N., Inazawa, J., Gonzalez, G., Aguilar-Bryan, L., Seino, S., Bryan, J. Science (1995) [Pubmed]
  23. Sulfonylurea receptor 1 and Kir6.2 expression in the novel human insulin-secreting cell line NES2Y. Macfarlane, W.M., O'Brien, R.E., Barnes, P.D., Shepherd, R.M., Cosgrove, K.E., Lindley, K.J., Aynsley-Green, A., James, R.F., Docherty, K., Dunne, M.J. Diabetes (2000) [Pubmed]
  24. Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses. van Dam, R.M., Hoebee, B., Seidell, J.C., Schaap, M.M., de Bruin, T.W., Feskens, E.J. Diabet. Med. (2005) [Pubmed]
  25. Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure. Dörschner, H., Brekardin, E., Uhde, I., Schwanstecher, C., Schwanstecher, M. Mol. Pharmacol. (1999) [Pubmed]
  26. Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects. Zünkler, B.J. Pharmacol. Ther. (2006) [Pubmed]
  27. Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate-sensitive potassium channels. Kawano, T., Oshita, S., Takahashi, A., Tsutsumi, Y., Tomiyama, Y., Kitahata, H., Kuroda, Y., Nakaya, Y. Anesthesiology (2004) [Pubmed]
  28. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. Stanik, J., Gasperikova, D., Paskova, M., Barak, L., Javorkova, J., Jancova, E., Ciljakova, M., Hlava, P., Michalek, J., Flanagan, S.E., Pearson, E., Hattersley, A.T., Ellard, S., Klimes, I. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  29. Four novel splice variants of sulfonylurea receptor 1. Hambrock, A., Preisig-Müller, R., Russ, U., Piehl, A., Hanley, P.J., Ray, J., Daut, J., Quast, U., Derst, C. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  30. K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits. Yoshida, H., Feig, J.E., Morrissey, A., Ghiu, I.A., Artman, M., Coetzee, W.A. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  31. PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. Béguin, P., Nagashima, K., Nishimura, M., Gonoi, T., Seino, S. EMBO J. (1999) [Pubmed]
  32. Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor. Magge, S.N., Shyng, S.L., MacMullen, C., Steinkrauss, L., Ganguly, A., Katz, L.E., Stanley, C.A. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  33. Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. Hansen, S.K., Nielsen, E.M., Ek, J., Andersen, G., Glümer, C., Carstensen, B., Mouritzen, P., Drivsholm, T., Borch-Johnsen, K., Jørgensen, T., Hansen, T., Pedersen, O. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  34. Molecular basis and characteristics of KATP channel in human corporal smooth muscle cells. Insuk, S.O., Chae, M.R., Choi, J.W., Yang, D.K., Sim, J.H., Lee, S.W. Int. J. Impot. Res. (2003) [Pubmed]
  35. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Massa, O., Iafusco, D., D'Amato, E., Gloyn, A.L., Hattersley, A.T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crinó, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. Hum. Mutat. (2005) [Pubmed]
  36. Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. Yokoi, N., Kanamori, M., Horikawa, Y., Takeda, J., Sanke, T., Furuta, H., Nanjo, K., Mori, H., Kasuga, M., Hara, K., Kadowaki, T., Tanizawa, Y., Oka, Y., Iwami, Y., Ohgawara, H., Yamada, Y., Seino, Y., Yano, H., Cox, N.J., Seino, S. Diabetes (2006) [Pubmed]
  37. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Gloyn, A.L., Weedon, M.N., Owen, K.R., Turner, M.J., Knight, B.A., Hitman, G., Walker, M., Levy, J.C., Sampson, M., Halford, S., McCarthy, M.I., Hattersley, A.T., Frayling, T.M. Diabetes (2003) [Pubmed]
  38. Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy. Ohkubo, K., Nagashima, M., Naito, Y., Taguchi, T., Suita, S., Okamoto, N., Fujinaga, H., Tsumura, K., Kikuchi, K., Ono, J. Clin. Endocrinol. (Oxf) (2005) [Pubmed]
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