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Gene Review

KCNJ6  -  potassium channel, inwardly rectifying...

Homo sapiens

Synonyms: BIR1, G protein-activated inward rectifier potassium channel 2, GIRK-2, GIRK2, Inward rectifier K(+) channel Kir3.2, ...
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Disease relevance of KCNJ6


Psychiatry related information on KCNJ6


High impact information on KCNJ6


Chemical compound and disease context of KCNJ6

  • Recently, we have demonstrated that potassium channels containing G-protein-activated potassium channel 2 (GIRK2) subunits play a significant role in hypothermia induced by several neurotransmitter receptor agonists, including the serotonin (5-HT)1A/5-HT7 receptor agonist 8-OH-DPAT [R-(+)-8-hydroxy-2-(di-n-propylamino) tetralin] [11].

Biological context of KCNJ6

  • A knockout mouse model deprived of functional KCNJ6 protein is susceptible to spontaneous and provoked seizures without showing the histological signs of neuronal cell death found in the weaver mouse [1].
  • A simple tandem repeat DNA polymorphism, D21S1255, was identified in the region of the KATP-2 gene, and linkage studies between this marker and NIDDM were carried out in a group of Mexican-American sib pairs with NIDDM [12].
  • An analysis of mutant channels expressed in Xenopus oocytes revealed two amino acid substitutions in the C-terminal domain of GIRK2, GIRK2(L344E) and GIRK2(G347H), that exhibited decreased carbachol-activated currents but significantly enhanced basal currents with coexpression of G(betagamma) subunits [13].
  • A yeast screen for active Kir3.2 channels subjected to random mutagenesis has identified residues in the transmembrane segments that are crucial for controlling the opening of Kir3.2 channels [14].
  • In this study, we made point mutations on suspected residues on these outer strands and investigated their ability to activate GIRK1/GIRK2 channels [15].

Anatomical context of KCNJ6

  • Human D3 receptors couple strongly to homomeric human GIRK2 channels coexpressed in Chinese hamster ovary (CHO) cells, with a coupling efficiency comparable to that of D2L receptors [16].
  • GIRK (1,3,4) mRNA expression was seen in three squamous cell lines, GIRK2 was only expressed in one squamous cell line [3].
  • Qualitative PCR demonstrated the presence of Kir3.1 and Kir3.2 transcripts in all smooth muscle cell preparations examined [17].
  • Here, we report that GIRK channels formed by GIRK1 and GIRK2 subunits are found in two large populations of lamina II excitatory interneurons [18].

Associations of KCNJ6 with chemical compounds

  • We found that a glutamate residue of GIRK2 (E315), located on a hydrophobic domain of the C terminus, is crucial for the channel activation [19].
  • Modification of E315C in GIRK2 and E304C in GIRK1 by sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES(-)) increased the current by approximately 17-fold, whereas modification by 2-aminoethyl methanethiosulfonate hydrochloride (MTSEA(+)), abolished the current [20].
  • This suggests that the aromatic ring of the tyrosine residue rather than its hydroxyl group is involved in maintaining the pore architecture of human GIRK2 channels [21].
  • 5. We conclude that Na+ directly interacts with Asp226 of GIRK2 to reduce the negative electrostatic potential and promote the functional interaction of the channels with PIP2 [22].
  • Changes in EC(50) values for the W318L and W318Y/H319Y mu-opioid receptors show a partial contribution of these residues to the decreased GIRK1/GIRK2 channel activation by fentanyl analogs through kappa- and delta-opioid receptors [23].

Physical interactions of KCNJ6

  • The mutated GIRK2 retained the ability to interact with G protein betagamma subunits, and it showed almost the same inwardly rectifying property as the wild type [19].

Regulatory relationships of KCNJ6

  • Together, these results suggest that the interaction of PTX-sensitive Galphai/o subunit with the GIRK2 C-terminal domain regulates G-protein receptor coupling, and may be important for establishing specific Galphai/o signaling pathways [24].

Other interactions of KCNJ6

  • The mutated GIRK1 and GIRK2 retained ion selectivity to K(+) ions [19].
  • There was no evidence for linkage between D21S1255 and NIDDM, indicating that KATP-2 is not a major susceptibility gene in this population [12].
  • Co-immunoprecipitation reveals that Galpha(q) binds with Kir3.2, but not with Kir2.2 or Kir2 [25].
  • 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 [26].
  • Other genes among the top signals were KCNJ6 and GABRA4 [27].

Analytical, diagnostic and therapeutic context of KCNJ6


  1. Mutation analysis of the inwardly rectifying K(+) channels KCNJ6 (GIRK2) and KCNJ3 (GIRK1) in juvenile myoclonic epilepsy. Hallmann, K., Durner, M., Sander, T., Steinlein, O.K. Am. J. Med. Genet. (2000) [Pubmed]
  2. Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes. Chioza, B., Osei-Lah, A., Wilkie, H., Nashef, L., McCormick, D., Asherson, P., Makoff, A.J. Epilepsy Res. (2002) [Pubmed]
  3. Expression of G-protein inwardly rectifying potassium channels (GIRKs) in lung cancer cell lines. Plummer, H.K., Dhar, M.S., Cekanova, M., Schuller, H.M. BMC Cancer (2005) [Pubmed]
  4. 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]
  5. The human homologue of the weaver mouse gene in familial and sporadic Parkinson's disease. Bandmann, O., Davis, M.B., Marsden, C.D., Wood, N.W. Neuroscience (1996) [Pubmed]
  6. Chromosome 21 KIR channels in brain development. Thiery, E., Thomas, S., Vacher, S., Delezoide, A.L., Delabar, J.M., Créau, N. J. Neural Transm. Suppl. (2003) [Pubmed]
  7. The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Speliotes, E.K., Uren, A., Vaux, D., Horvitz, H.R. Mol. Cell (2000) [Pubmed]
  8. G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Lewohl, J.M., Wilson, W.R., Mayfield, R.D., Brozowski, S.J., Morrisett, R.A., Harris, R.A. Nat. Neurosci. (1999) [Pubmed]
  9. K+ channel selectivity depends on kinetic as well as thermodynamic factors. Grabe, M., Bichet, D., Qian, X., Jan, Y.N., Jan, L.Y. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. BIR-1, a Caenorhabditis elegans homologue of Survivin, regulates transcription and development. Kostrouchova, M., Kostrouch, Z., Saudek, V., Piatigorsky, J., Rall, J.E. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  11. Hypothermic responses to 8-OH-DPAT in the Ts65Dn mouse model of Down syndrome. Stasko, M.R., Scott-McKean, J.J., Costa, A.C. Neuroreport (2006) [Pubmed]
  12. 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]
  13. betaL-betaM loop in the C-terminal domain of G protein-activated inwardly rectifying K(+) channels is important for G(betagamma) subunit activation. Finley, M., Arrabit, C., Fowler, C., Suen, K.F., Slesinger, P.A. J. Physiol. (Lond.) (2004) [Pubmed]
  14. Controlling potassium channel activities: Interplay between the membrane and intracellular factors. Yi, B.A., Minor, D.L., Lin, Y.F., Jan, Y.N., Jan, L.Y. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  15. Interaction of G protein beta subunit with inward rectifier K(+) channel Kir3. Zhao, Q., Kawano, T., Nakata, H., Nakajima, Y., Nakajima, S., Kozasa, T. Mol. Pharmacol. (2003) [Pubmed]
  16. Human dopamine D3 and D2L receptors couple to inward rectifier potassium channels in mammalian cell lines. Kuzhikandathil, E.V., Yu, W., Oxford, G.S. Mol. Cell. Neurosci. (1998) [Pubmed]
  17. 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]
  18. Distinct Populations of Spinal Cord Lamina II Interneurons Expressing G-Protein-Gated Potassium Channels. Marker, C.L., Luj??n, R., Col??n, J., Wickman, K. J. Neurosci. (2006) [Pubmed]
  19. A glutamate residue at the C terminus regulates activity of inward rectifier K+ channels: implication for Andersen's syndrome. Chen, L., Kawano, T., Bajic, S., Kaziro, Y., Itoh, H., Art, J.J., Nakajima, Y., Nakajima, S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  20. A role for the middle C terminus of G-protein-activated inward rectifier potassium channels in regulating gating. Guo, Y., Waldron, G.J., Murrell-Lagnado, R. J. Biol. Chem. (2002) [Pubmed]
  21. Dominant-negative mutants identify a role for GIRK channels in D3 dopamine receptor-mediated regulation of spontaneous secretory activity. Kuzhikandathil, E.V., Oxford, G.S. J. Gen. Physiol. (2000) [Pubmed]
  22. Molecular mechanism for sodium-dependent activation of G protein-gated K+ channels. Ho, I.H., Murrell-Lagnado, R.D. J. Physiol. (Lond.) (1999) [Pubmed]
  23. Interaction of p-fluorofentanyl on cloned human opioid receptors and exploration of the role of Trp-318 and His-319 in mu-opioid receptor selectivity. Ulens, C., Van Boven, M., Daenens, P., Tytgat, J. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  24. Pertussis-toxin-sensitive Galpha subunits selectively bind to C-terminal domain of neuronal GIRK channels: evidence for a heterotrimeric G-protein-channel complex. Clancy, S.M., Fowler, C.E., Finley, M., Suen, K.F., Arrabit, C., Berton, F., Kosaza, T., Casey, P.J., Slesinger, P.A. Mol. Cell. Neurosci. (2005) [Pubmed]
  25. Signal transduction pathway for the substance P-induced inhibition of rat Kir3 (GIRK) channel. Koike-Tani, M., Collins, J.M., Kawano, T., Zhao, P., Zhao, Q., Kozasa, T., Nakajima, S., Nakajima, Y. J. Physiol. (Lond.) (2005) [Pubmed]
  26. 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]
  27. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Saccone, S.F., Hinrichs, A.L., Saccone, N.L., Chase, G.A., Konvicka, K., Madden, P.A., Breslau, N., Johnson, E.O., Hatsukami, D., Pomerleau, O., Swan, G.E., Goate, A.M., Rutter, J., Bertelsen, S., Fox, L., Fugman, D., Martin, N.G., Montgomery, G.W., Wang, J.C., Ballinger, D.G., Rice, J.P., Bierut, L.J. Hum. Mol. Genet. (2007) [Pubmed]
  28. Serine 329 of the mu-opioid receptor interacts differently with agonists. Pil, J., Tytgat, J. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
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