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Gene Review

KCNJ5  -  potassium channel, inwardly rectifying...

Homo sapiens

Synonyms: CIR, Cardiac inward rectifier, G protein-activated inward rectifier potassium channel 4, GIRK-4, GIRK4, ...
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Disease relevance of KCNJ5


Psychiatry related information on KCNJ5


High impact information on KCNJ5

  • Two KIR6.x genes and two SUR genes have been identified, and combinations of subunits give rise to KATP channel subtypes found in pancreatic beta-cells, neurons, and cardiac, skeletal, and smooth muscle [7].
  • Adenosine 5'-triphosphate-sensitive potassium (KATP) channels couple metabolic events to membrane electrical activity in a variety of cell types [7].
  • In anoxic cardiac ventricular muscle KATP channels are believed to be responsible for shortening the action potential, and it has been proposed that a fall in ATP concentration during metabolic exhaustion increases the activity of KATP channels in skeletal muscle, which may reduce excitability [8].
  • This concentration is much higher than the intracellular ATP concentration required to half block the KATP-channel current in either cardiac muscle (0.1 mM) or skeletal muscle (0.14 mM), indicating that the open-state probability of KATP channels is normally very low in intact muscle [8].
  • Decreases in the ADP level as glucose is metabolized result in KATP channel closure [9].

Chemical compound and disease context of KCNJ5

  • The key role KATP channel play in the regulation of insulin secretion in response to changes in glucose metabolism is underscored by the finding that a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in KATP channel subunits that result in the loss of channel activity [9].
  • During steady-state vasoconstriction induced in isolated ferret lungs by moderate hypoxia, cromakalim caused dose-dependent vasodilation (EC50 = 7 x 10(-7) M) which was reversed by glibenclamide (IC50 = 8 x 10(-7) M), indicating that KATP channels were present and capable of modulating vascular tone [10].
  • These findings suggest that in the ferret lung (a) severe hypoxia decreased ATP concentration and thereby opened KATP channels, resulting in increased K+ efflux, hyperpolarization, vasodilation, and reversal of the initial vasoconstrictor response; and (b) hyperglycemia prevented this sequence of events [10].
  • CONCLUSIONS: In humans, ischemic preconditioning during brief repeated coronary occlusions is completely abolished by pretreatment with glibenclamide, thus suggesting that it is mainly mediated by KATP channels [11].
  • KATP channels also are found in the heart where they are involved in the response to cardiac ischemia: they also are blocked by phentolamine [12].

Biological context of KCNJ5

  • Assignment of KATP-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24 [13].
  • Isolation of a cDNA clone encoding a KATP channel-like protein expressed in insulin-secreting cells, localization of the human gene to chromosome band 21q22.1, and linkage studies with NIDDM [1].
  • GIRK1 membrane-spanning domain 1 was required for optimal glycosylation at Asn(119) because a chimera that contained GIRK4 membrane-spanning domain 1 significantly reduced the addition of a carbohydrate structure at this site [14].
  • We have analyzed a series of mutant and chimeric channels suggesting that the GIRK4 subunit is capable of responding to G(q) signals and that the resulting current inhibition does not occur via phosphorylation of a canonical PKC site on the channel itself [15].
  • Single-channel recordings of the active chimeras exhibited patterns of activities with open-time kinetics and conductance characteristics representative of those of GIRK4, indicating that the presence of the GIRK1 C-terminal region caused an increase in the frequency of channel openings without affecting their duration [16].

Anatomical context of KCNJ5


Associations of KCNJ5 with chemical compounds

  • The metabolism of glucose in insulin-secreting cells leads to closure of ATP-sensitive K+ channels (KATP), an event that initiates the insulin secretory process [1].
  • We show that mutation of charged glutamate and arginine residues behind the selectivity filter in the Kir3.1/Kir3.4 K+ channel reduces or abolishes K+ selectivity, comparable with previously reported effects in the Kir2.1 K+ channel [20].
  • Complementary mutation of the equivalent amino acid in Kir3.4 to produce Kir3.4(S143T)(D223N) significantly reduced the sensitivity of the channel to arachidonic acid- and Et-1-induced inhibition [21].
  • RESULTS: mRNA levels of transient outward channel (Kv4.3), acetylcholine-dependent potassium channel (Kir3.4) and ATP-dependent potassium channel (Kir6.2) were reduced in patients with persistent AF (-35%, -47% and -36%, respectively, p < 0.05), whereas only Kv4.3 mRNA level was reduced in patients with paroxysmal AF (-29%, p = 0.03) [22].
  • Effects of ACh and adenosine mediated by Kir3.1 and Kir3.4 on ferret ventricular cells [23].

Physical interactions of KCNJ5

  • Moreover, mutations at these GIRK4 sites reduced significantly binding of the channel domains to G beta gamma . The corresponding residues in GIRK1 also showed a critical involvement in G beta gamma sensitivity [24].

Other interactions of KCNJ5

  • The single-point mutant GIRK4(S143F) behaved as a GIRK1 analog, forming multimers with GIRK2, GIRK4, or GIRK5 channels that exhibited prolonged single-channel open-time duration and enhanced activity compared with that of homomultimers [25].
  • This finding may partly account for the reason that GIRK4 is not glycosylated at Asn(132), either as a homomer or when coexpressed with GIRK1 [14].
  • Transcripts for Kir3.3 and Kir3.4 were not detected in the same preparations [26].
  • Considerable genetic, molecular, physiological and pharmacological evidence now exists to support a role for K(+) channels such as KCNQ2/Q3, Kv1.1, KATP and GIRK2 in the control of neuronal excitability and epileptogenesis [27].
  • In a multivariable analysis, high ERG expression (P < .001) and the presence of MLL PTD (P = .027) predicted worse CIR [28].

Analytical, diagnostic and therapeutic context of KCNJ5


  1. Isolation of a cDNA clone encoding a KATP channel-like protein expressed in insulin-secreting cells, localization of the human gene to chromosome band 21q22.1, and linkage studies with NIDDM. Tsaur, M.L., Menzel, S., Lai, F.P., Espinosa, R., Concannon, P., Spielman, R.S., Hanis, C.L., Cox, N.J., Le Beau, M.M., German, M.S. Diabetes (1995) [Pubmed]
  2. Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines. Plummer, H.K., Yu, Q., Cakir, Y., Schuller, H.M. BMC Cancer (2004) [Pubmed]
  3. Isolation and chromosomal localization of a human ATP-regulated potassium channel. Krishnan, S.N., Desai, T., Ward, D.C., Haddad, G.G. Hum. Genet. (1995) [Pubmed]
  4. 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]
  5. Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Kane, C., Shepherd, R.M., Squires, P.E., Johnson, P.R., James, R.F., Milla, P.J., Aynsley-Green, A., Lindley, K.J., Dunne, M.J. Nat. Med. (1996) [Pubmed]
  6. A KATP-channel opener as a potential treatment modality for erectile dysfunction. Moon, D.G., Byun, H.S., Kim, J.J. BJU international. (1999) [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. Modulation of ATP-sensitive K+ channels in skeletal muscle by intracellular protons. Davies, N.W. Nature (1990) [Pubmed]
  9. Molecular biology of adenosine triphosphate-sensitive potassium channels. Aguilar-Bryan, L., Bryan, J. Endocr. Rev. (1999) [Pubmed]
  10. ATP-dependent K+ channels modulate vasoconstrictor responses to severe hypoxia in isolated ferret lungs. Wiener, C.M., Dunn, A., Sylvester, J.T. J. Clin. Invest. (1991) [Pubmed]
  11. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Tomai, F., Crea, F., Gaspardone, A., Versaci, F., De Paulis, R., Penta de Peppo, A., Chiariello, L., Gioffrè, P.A. Circulation (1994) [Pubmed]
  12. Phentolamine block of KATP channels is mediated by Kir6.2. Proks, P., Ashcroft, F.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  13. Assignment of KATP-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24. Tucker, S.J., James, M.R., Adelman, J.P. Genomics (1995) [Pubmed]
  14. Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different consequences in potassium channel function. Pabon, A., Chan, K.W., Sui, J.L., Wu, X., Logothetis, D.E., Thornhill, W.B. J. Biol. Chem. (2000) [Pubmed]
  15. Inhibition of a Gi-activated potassium channel (GIRK1/4) by the Gq-coupled m1 muscarinic acetylcholine receptor. Hill, J.J., Peralta, E.G. J. Biol. Chem. (2001) [Pubmed]
  16. Specific regions of heteromeric subunits involved in enhancement of G protein-gated K+ channel activity. Chan, K.W., Sui, J.L., Vivaudou, M., Logothetis, D.E. J. Biol. Chem. (1997) [Pubmed]
  17. A G-protein-activated inwardly rectifying K+ channel (GIRK4) from human hippocampus associates with other GIRK channels. Spauschus, A., Lentes, K.U., Wischmeyer, E., Dissmann, E., Karschin, C., Karschin, A. J. Neurosci. (1996) [Pubmed]
  18. Diverse trafficking patterns due to multiple traffic motifs in G protein-activated inwardly rectifying potassium channels from brain and heart. Ma, D., Zerangue, N., Raab-Graham, K., Fried, S.R., Jan, Y.N., Jan, L.Y. Neuron (2002) [Pubmed]
  19. Tissue-specific regulation of G-protein-coupled inwardly rectifying K+ channel expression by muscarinic receptor activation in ovo. Thomas, S.L., Chmelar, R.S., Lu, C., Halvorsen, S.W., Nathanson, N.M. J. Biol. Chem. (1997) [Pubmed]
  20. Molecular basis of ion selectivity, block, and rectification of the inward rectifier Kir3.1/Kir3.4 K(+) channel. Dibb, K.M., Rose, T., Makary, S.Y., Claydon, T.W., Enkvetchakul, D., Leach, R., Nichols, C.G., Boyett, M.R. J. Biol. Chem. (2003) [Pubmed]
  21. Eicosanoids inhibit the G-protein-gated inwardly rectifying potassium channel (Kir3) at the Na+/PIP2 gating site. Rogalski, S.L., Chavkin, C. J. Biol. Chem. (2001) [Pubmed]
  22. Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels. Brundel, B.J., Van Gelder, I.C., Henning, R.H., Tuinenburg, A.E., Wietses, M., Grandjean, J.G., Wilde, A.A., Van Gilst, W.H., Crijns, H.J. J. Am. Coll. Cardiol. (2001) [Pubmed]
  23. Effects of ACh and adenosine mediated by Kir3.1 and Kir3.4 on ferret ventricular cells. Dobrzynski, H., Janvier, N.C., Leach, R., Findlay, J.B., Boyett, M.R. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
  24. Identification of critical residues controlling G protein-gated inwardly rectifying K(+) channel activity through interactions with the beta gamma subunits of G proteins. He, C., Yan, X., Zhang, H., Mirshahi, T., Jin, T., Huang, A., Logothetis, D.E. J. Biol. Chem. (2002) [Pubmed]
  25. Control of channel activity through a unique amino acid residue of a G protein-gated inwardly rectifying K+ channel subunit. Chan, K.W., Sui, J.L., Vivaudou, M., Logothetis, D.E. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  26. Kir3.1/3.2 encodes an I(KACh)-like current in gastrointestinal myocytes. Bradley, K.K., Hatton, W.J., Mason, H.S., Walker, R.L., Flynn, E.R., Kenyon, J.L., Horowitz, B. Am. J. Physiol. Gastrointest. Liver Physiol. (2000) [Pubmed]
  27. Potassium channels as anti-epileptic drug targets. Wickenden, A.D. Neuropharmacology (2002) [Pubmed]
  28. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. Marcucci, G., Baldus, C.D., Ruppert, A.S., Radmacher, M.D., Mrózek, K., Whitman, S.P., Kolitz, J.E., Edwards, C.G., Vardiman, J.W., Powell, B.L., Baer, M.R., Moore, J.O., Perrotti, D., Caligiuri, M.A., Carroll, A.J., Larson, R.A., de la Chapelle, A., Bloomfield, C.D. J. Clin. Oncol. (2005) [Pubmed]
  29. Cs+ block of the cardiac muscarinic K+ channel, GIRK1/GIRK4, is not dependent on the aspartate residue at position 173. Dibb, K.M., Leach, R., Lancaster, M.K., Findlay, J.B., Boyett, M.R. Pflugers Arch. (2000) [Pubmed]
  30. Ischemic preconditioning: from adenosine receptor to KATP channel. Cohen, M.V., Baines, C.P., Downey, J.M. Annu. Rev. Physiol. (2000) [Pubmed]
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