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Gene Review

Kcnj5  -  potassium inwardly-rectifying channel,...

Mus musculus

Synonyms: CIR, Cardiac inward rectifier, G protein-activated inward rectifier potassium channel 4, GIRK-4, GIRK4, ...
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Disease relevance of Kcnj5

  • Both Kir3.1 knock-out and Kir3.4 knock-out mice exhibited mild resting tachycardias and blunted responses to pharmacological manipulation intended to activate I(KACh) [1].
  • Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity [2].
  • KATP channel function is found to be impaired in the beta cells of transgenic mice with hyperglycemia [3].
  • Hyperinsulinism induced by targeted suppression of beta cell KATP channels [4].
  • Thus, intact KATP channel function is mandatory for adequate repolarization under sympathetic stress providing electrical tolerance against triggered arrhythmia [5].

Psychiatry related information on Kcnj5

  • Mice lacking GIRK4 were viable and appeared normal and did not display gross deficiencies in locomotor activity, visual tasks, and pain perception [6].

High impact information on Kcnj5

  • It is now clear that stimulation of insulin release by fuel secretagogues, such as glucose, involves the closure of K+ channels that are sensitive to the intracellular ATP concentration (KATP channels) [7].
  • Here we show that adrenaline suppresses B-cell electrical activity (and thus insulin secretion) by a G protein-dependent mechanism, which culminates in the activation of a sulphonylurea-insensitive low-conductance K+ channel distinct from the KATP channel [7].
  • The molecular mechanisms involved are not fully understood but are believed to involve inhibition of potassium channels sensitive to adenosine triphosphate (KATP channels) in the beta cell membrane, causing membrane depolarization, calcium influx, and activation of the secretory machinery [8].
  • Thus, our results demonstrate that KATP channels are important in glucose sensing in VMH GR neurons, and are essential for the maintenance of glucose homeostasis [9].
  • At early stages, IK,ACh is primarily formed by Kir3.1, while in late embryonic and adult cells, Kir3.4 is the predominant subunit [10].

Chemical compound and disease context of Kcnj5

  • We conclude that epinephrine can hyperpolarize beta-cells in the absence of KATP channels via activation of low-conductance BaCl2-sensitive K+ channels that are regulated by pertussis toxin-sensitive G proteins [11].
  • The blocker of mitochondrial KATP channel, 5-hydroxydecanoate (5-HD, 100 microM) was given 10 min before ischemia [12].
  • Here we examined the opening effect of KR-31378 on the KATP channel using patch clamp recording in neuroblastoma 2a (N2a) cells and investigated the neuroprotective effect of KR-31378 in organotypic hippocampal slice cultures exposed to oxygen/glucose deprivation [13].
  • Though activate adenosine A1 receptor coupled with Gi protein can open the KATP channels, adenosine is quickly released during ischemia and exerts potent coronary vasodilatation to maintain coronary blood flow through A2 receptors [14].

Biological context of Kcnj5

  • The pancreatic islet CIR and GIRK2 full-length cDNAs were cloned, and their genes were localized to human chromosomes 11q23-ter and 21, respectively [15].
  • Partial structure, chromosome localization, and expression of the mouse Girk4 gene [16].
  • To assess the role of I(KACh) in heart rate regulation in vivo, we generated a mouse line deficient in I(KACh) by targeted disruption of the gene coding for GIRK4, one of the channel subunits [17].
  • In addition to these effects, sulfonylureas also promoted exocytosis by direct interaction with the secretory machinery not involving closure of the plasma membrane KATP channels [8].
  • ATP-sensitive K+ (KATP) channels regulate many cellular functions by linking cell metabolism to membrane potential [18].

Anatomical context of Kcnj5


Associations of Kcnj5 with chemical compounds

  • Here we show that in cardiac as well as in cloned KATP channels (Kir6.2 + sulfonylurea receptor) polyamine-mediated rectification is not fixed but changes with intracellular pH in the physiological range: inward-rectification is prominent at basic pH, while at acidic pH rectification is very weak [22].
  • Nuclear KATP channels trigger nuclear Ca(2+) transients that modulate nuclear function [23].
  • We have generated transgenic mice expressing a dominant-negative form of the KATP channel subunit Kir6.2 (Kir6.2G132S, substitution of glycine with serine at position 132) in pancreatic beta cells [3].
  • Using digital video imaging of fura-2--loaded islets, we have analyzed the spatial distribution of [Ca2+]i in response to the natural secretagogue glucose and the KATP channel blocker tolbutamide [24].
  • When KATP channels were held open with diazoxide (and the plasma membrane partially depolarized with high extracellular KCl), amino acids still stimulated insulin release [25].

Regulatory relationships of Kcnj5

  • We conclude that Kir3.1 confers properties to I(KACh) that enhance channel activity and that Kir3.4 homomultimers do not contribute significantly to the muscarinic-gated potassium current [1].

Other interactions of Kcnj5

  • Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4 [6].
  • Northern blot analysis detected CIR mRNA at similar levels in human islets and exocrine pancreas, while the abundance of GIRK2 mRNA in the two tissues was insufficient for detection by this method [15].
  • Hot-plate paw-lick latencies for wild-type, Kir3.2 knockout, Kir3.3 knockout, and Kir3.4 knockout mice were measured at 52 degrees C and 55 degrees C, following the s.c. injection of either saline or 10 mg/kg morphine [26].
  • ATP-sensitive potassium (KATP) channels are formed by the coassembly of four Kir6.2 subunits and four sulfonylurea receptor subunits (SUR) [27].
  • The role of Kir2.1 in the genesis of native cardiac inward-rectifier K+ currents during pre- and postnatal development [28].

Analytical, diagnostic and therapeutic context of Kcnj5

  • Western blot analysis revealed that platelets express GIRK1, GIRK2, and GIRK4 [29].
  • In the present study we have used the patch-clamp technique to study the direct effects of alpha-ketoisocaproate on the KATP channel in isolated patches and intact pancreatic beta-cells [30].
  • Glibenclamide (50 micrograms, ICV), a selective adenosine triphosphate-sensitive potassium (KATP) channel blocker, in combination with SC saline hardly affected the rectal temperature compared to the control group [31].
  • From these results, we demonstrated that KATP channels play an important role as indirect modulators of the supraspinal analgesia induced by mu agonist but not kappa agonist in mice, and the activation of descending noradrenergic system induced by i.c.v. morphine appears to be suppressed by the blockade of KATP channels [32].
  • Activation of ATP-sensitive potassium (KATP) channels is known to have cardioprotective effects during periods of ischemia and reperfusion, making these channels important targets for clinical drug discovery [33].


  1. Contribution of the Kir3.1 subunit to the muscarinic-gated atrial potassium channel IKACh. Bettahi, I., Marker, C.L., Roman, M.I., Wickman, K. J. Biol. Chem. (2002) [Pubmed]
  2. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. Plum, L., Ma, X., Hampel, B., Balthasar, N., Coppari, R., Münzberg, H., Shanabrough, M., Burdakov, D., Rother, E., Janoschek, R., Alber, J., Belgardt, B.F., Koch, L., Seibler, J., Schwenk, F., Fekete, C., Suzuki, A., Mak, T.W., Krone, W., Horvath, T.L., Ashcroft, F.M., Brüning, J.C. J. Clin. Invest. (2006) [Pubmed]
  3. Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. Miki, T., Tashiro, F., Iwanaga, T., Nagashima, K., Yoshitomi, H., Aihara, H., Nitta, Y., Gonoi, T., Inagaki, N., Miyazaki, J., Seino, S. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  4. Hyperinsulinism induced by targeted suppression of beta cell KATP channels. Koster, J.C., Remedi, M.S., Flagg, T.P., Johnson, J.D., Markova, K.P., Marshall, B.A., Nichols, C.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  5. Genetic disruption of Kir6.2, the pore-forming subunit of ATP-sensitive K+ channel, predisposes to catecholamine-induced ventricular dysrhythmia. Liu, X.K., Yamada, S., Kane, G.C., Alekseev, A.E., Hodgson, D.M., O'Cochlain, F., Jahangir, A., Miki, T., Seino, S., Terzic, A. Diabetes (2004) [Pubmed]
  6. Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4. Wickman, K., Karschin, C., Karschin, A., Picciotto, M.R., Clapham, D.E. J. Neurosci. (2000) [Pubmed]
  7. Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic B cells. Rorsman, P., Bokvist, K., Ammälä, C., Arkhammar, P., Berggren, P.O., Larsson, O., Wåhlander, K. Nature (1991) [Pubmed]
  8. PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic beta cells. Eliasson, L., Renström, E., Ammälä, C., Berggren, P.O., Bertorello, A.M., Bokvist, K., Chibalin, A., Deeney, J.T., Flatt, P.R., Gäbel, J., Gromada, J., Larsson, O., Lindström, P., Rhodes, C.J., Rorsman, P. Science (1996) [Pubmed]
  9. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Miki, T., Liss, B., Minami, K., Shiuchi, T., Saraya, A., Kashima, Y., Horiuchi, M., Ashcroft, F., Minokoshi, Y., Roeper, J., Seino, S. Nat. Neurosci. (2001) [Pubmed]
  10. Differential subunit composition of the G protein-activated inward-rectifier potassium channel during cardiac development. Fleischmann, B.K., Duan, Y., Fan, Y., Schoneberg, T., Ehlich, A., Lenka, N., Viatchenko-Karpinski, S., Pott, L., Hescheler, J., Fakler, B. J. Clin. Invest. (2004) [Pubmed]
  11. Epinephrine-induced hyperpolarization of islet cells without KATP channels. Sieg, A., Su, J., Muñoz, A., Buchenau, M., Nakazaki, M., Aguilar-Bryan, L., Bryan, J., Ullrich, S. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  12. Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. Khan, S., Salloum, F., Das, A., Xi, L., Vetrovec, G.W., Kukreja, R.C. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  13. Neuroprotective effect of KR-31378 via KATP channel opening against ischemic insult. Won, R., Lim, J.Y., Lee, S.Y., Park, J.H., Sohn, N.W. Biol. Pharm. Bull. (2004) [Pubmed]
  14. ATP sensitive potassium channel and myocardial preconditioning. Day, Y.J., Gao, Z., Tan, P.C., Linden, J. Acta Anaesthesiol. Sin. (1999) [Pubmed]
  15. Pancreatic islet cells express a family of inwardly rectifying K+ channel subunits which interact to form G-protein-activated channels. Ferrer, J., Nichols, C.G., Makhina, E.N., Salkoff, L., Bernstein, J., Gerhard, D., Wasson, J., Ramanadham, S., Permutt, A. J. Biol. Chem. (1995) [Pubmed]
  16. Partial structure, chromosome localization, and expression of the mouse Girk4 gene. Wickman, K., Seldin, M.F., Gendler, S.J., Clapham, D.E. Genomics (1997) [Pubmed]
  17. Abnormal heart rate regulation in GIRK4 knockout mice. Wickman, K., Nemec, J., Gendler, S.J., Clapham, D.E. Neuron (1998) [Pubmed]
  18. Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Miki, T., Nagashima, K., Tashiro, F., Kotake, K., Yoshitomi, H., Tamamoto, A., Gonoi, T., Iwanaga, T., Miyazaki, J., Seino, S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  19. Expression of GIRK (Kir3.1/Kir3.4) channels in mouse fibroblast cells with and without beta1 integrins. Ivanina, T., Neusch, C., Li, Y.X., Tong, Y., Labarca, C., Mosher, D.F., Lester, H.A. FEBS Lett. (2000) [Pubmed]
  20. Interaction between the RGS domain of RGS4 with G protein alpha subunits mediates the voltage-dependent relaxation of the G protein-gated potassium channel. Inanobe, A., Fujita, S., Makino, Y., Matsushita, K., Ishii, M., Chachin, M., Kurachi, Y. J. Physiol. (Lond.) (2001) [Pubmed]
  21. Regulation of muscarinic receptor expression and function in cultured cells and in knock-out mice. McKinnon, L.A., Rosoff, M., Hamilton, S.E., Schlador, M.L., Thomas, S.L., Nathanson, N.M. Life Sci. (1997) [Pubmed]
  22. Inward rectification in KATP channels: a pH switch in the pore. Baukrowitz, T., Tucker, S.J., Schulte, U., Benndorf, K., Ruppersberg, J.P., Fakler, B. EMBO J. (1999) [Pubmed]
  23. Nuclear KATP channels trigger nuclear Ca(2+) transients that modulate nuclear function. Quesada, I., Rovira, J.M., Martin, F., Roche, E., Nadal, A., Soria, B. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  24. Fluorescence digital image analysis of glucose-induced [Ca2+]i oscillations in mouse pancreatic islets of Langerhans. Valdeolmillos, M., Nadal, A., Soria, B., García-Sancho, J. Diabetes (1993) [Pubmed]
  25. Effects of glucose and amino acids on free ADP in betaHC9 insulin-secreting cells. Ronner, P., Naumann, C.M., Friel, E. Diabetes (2001) [Pubmed]
  26. Hyperalgesia and blunted morphine analgesia in G protein-gated potassium channel subunit knockout mice. Marker, C.L., Cintora, S.C., Roman, M.I., Stoffel, M., Wickman, K. Neuroreport (2002) [Pubmed]
  27. Stabilization of the activity of ATP-sensitive potassium channels by ion pairs formed between adjacent Kir6.2 subunits. Lin, Y.W., Jia, T., Weinsoft, A.M., Shyng, S.L. J. Gen. Physiol. (2003) [Pubmed]
  28. The role of Kir2.1 in the genesis of native cardiac inward-rectifier K+ currents during pre- and postnatal development. Nakamura, T.Y., Lee, K., Artman, M., Rudy, B., Coetzee, W.A. Ann. N. Y. Acad. Sci. (1999) [Pubmed]
  29. Role of G protein-gated inwardly rectifying potassium channels in P2Y12 receptor-mediated platelet functional responses. Shankar, H., Murugappan, S., Kim, S., Jin, J., Ding, Z., Wickman, K., Kunapuli, S.P. Blood (2004) [Pubmed]
  30. Direct inhibition of the pancreatic beta-cell ATP-regulated potassium channel by alpha-ketoisocaproate. Bränström, R., Efendić, S., Berggren, P.O., Larsson, O. J. Biol. Chem. (1998) [Pubmed]
  31. Role of central ATP-sensitive potassium channels in the hyperthermic effect of morphine in mice. Narita, M., Suzuki, T., Misawa, M., Nagase, H. Psychopharmacology (Berl.) (1992) [Pubmed]
  32. Role of central ATP-sensitive potassium channels in the analgesic effect and spinal noradrenaline turnover-enhancing effect of intracerebroventricularly injected morphine in mice. Narita, M., Suzuki, T., Misawa, M., Nagase, H., Nabeshima, A., Ashizawa, T., Ozawa, H., Saito, T., Takahata, N. Brain Res. (1992) [Pubmed]
  33. Identification and pharmacological characterization of sarcolemmal ATP-sensitive potassium channels in the murine atrial HL-1 cell line. Fox, J.E., Jones, L., Light, P.E. J. Cardiovasc. Pharmacol. (2005) [Pubmed]
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