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Gene Review

Kcnj3  -  potassium inwardly-rectifying channel,...

Mus musculus

Synonyms: G protein-activated inward rectifier potassium channel 1, GIRK-1, GIRK1, Girk1, Inward rectifier K(+) channel Kir3.1, ...
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Disease relevance of Kcnj3

  • Our results suggest that inhibition of both types of GIRK channels by these drugs underlies some of the side effects, in particular seizures and sinus tachycardia, observed in clinical practice [1].
  • The adenosine-induced GIRK currents were abolished by injection of pertussis toxin and CPA inhibited forskolin-stimulated cyclic AMP accumulation [2].
  • Consistent with these findings, GIRK1 knock-out and GIRK2 knock-out mice exhibited hyperalgesia in the tail-flick test of thermal nociception [3].
  • 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) [4].
  • Immunoblot analysis of transfected human embryonic kidney cells (HEK293) and mouse insulinoma cells (beta TC3) revealed several GIRK1-cp polypeptides, including the major 59-kDa band, corresponding to the predicted mass of the GIRK1 polypeptide plus the epitope tag [5].

High impact information on Kcnj3

  • These results explain in structural and chemical terms the basis of inward rectification, and they also have implications for G protein regulation of GIRK channels [6].
  • These results suggest that the GIRK channels in the brain and heart are important target sites for ethanol [7].
  • Here we show that ethanol opens G-protein-activated, inwardly rectifying K + (GIRK) channels, which has important implications for inhibitory regulation of neuronal excitability and heart rate [7].
  • At pharmacologically relevant concentrations, ethanol activated both brain-type GIRK1/2 and cardiac-type GIRK1/4 channels without interaction with G proteins or second messengers [7].
  • At early stages, IK,ACh is primarily formed by Kir3.1, while in late embryonic and adult cells, Kir3.4 is the predominant subunit [8].

Biological context of Kcnj3

  • 5. We demonstrate that fluoxetine, at low micromolar concentrations, inhibits GIRK channels that play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate through activation of various G-protein-coupled receptors [9].
  • In this study, we identify key features of the four mouse Girk genes including sequence, intron/exon structures, alternative splicing events, and candidate transcriptional start points [10].
  • Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single-channel conductance compared with diploid [11].
  • The mouse Girk genes are organized similarly, each containing four to seven exons [10].
  • Mutation of the aspartate (D) of RGD impaired currents, GIRK glycosylation, and membrane localization, but the interaction with beta1 integrins remained intact [12].

Anatomical context of Kcnj3

  • Both channel proteins are functionally expressed in Xenopus oocytes upon injection of their cRNA, alone or in combination with the GIRK1 cRNA [13].
  • Expression of GIRK (Kir3.1/Kir3.4) channels in mouse fibroblast cells with and without beta1 integrins [12].
  • Neither plasma membrane localization nor agonist-evoked GIRK currents were affected by the absence of beta1 integrins or by incubation with externally applied RGD-containing peptide [12].
  • We expressed GIRK1/GIRK4 channels labeled with green fluorescent protein in fibroblast cell lines expressing or lacking beta1 integrins [12].
  • In the hippocampus, all three neuronal GIRK subunits were detected [14].

Associations of Kcnj3 with chemical compounds

  • 4. The GIRK currents induced by ethanol were also attenuated in the presence of fluoxetine [9].
  • The present results suggest that inhibition of GIRK channels by fluoxetine may contribute to some of its therapeutic effects and adverse side effects, particularly seizures in overdose, observed in clinical practice [9].
  • Furthermore, in oocytes expressing GIRK1/2 channels and the cloned Xenopus A(1) adenosine receptor, GIRK current responses activated by the receptor were inhibited by fluoxetine [9].
  • G protein-activated K+ channel (GIRK) subunits possess a conserved extracellular integrin-binding motif (RGD) and bind directly to beta1 integrins [12].
  • 3. The inhibitory effect on GIRK channels was not obtained by intracellularly applied fluoxetine, and not affected by extracellular pH, which changed the proportion of the uncharged to protonated fluoxetine, suggesting that fluoxetine inhibits GIRK channels from the extracellular side [9].

Physical interactions of Kcnj3

  • Low level channel activity resembling recombinant Kir3.4 homomultimers was observed in 40% of the cell-attached patches from Kir3.1 knock-out myocytes [4].

Regulatory relationships of Kcnj3


Other interactions of Kcnj3

  • Multiple mRNA variants of Girk1, Girk3, and Girk4 were identified, existing by virtue of alternative splicing and/or usage of distinct transcription initiation sites [10].
  • Recently, it has been demonstrated that a point mutation in the GIRK2 gene, one of the GIRK family members, is the cause of the neurological and reproductive defects observed in the weaver (wv) mutant mouse [17].
  • MbIRK3 shows around 65% amino acid identity with IRK1 and rbIRK2 and only 50% with ROMK1 and GIRK1 [18].
  • K(G) channels are composed of combinations of four subunits termed G protein-gated inwardly rectifying K(+) channels (GIRK) [19].
  • Recently a family of GTPase activating proteins known as regulators of G-protein signaling were shown to be the missing link for the fast deactivation kinetics of GIRK channels in native cells, which contrast with the slow kinetics observed in heterologously expressed channels [20].

Analytical, diagnostic and therapeutic context of Kcnj3


  1. Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes. Kobayashi, T., Ikeda, K., Kumanishi, T. Br. J. Pharmacol. (2000) [Pubmed]
  2. Functional characterization of an endogenous Xenopus oocyte adenosine receptor. Kobayashi, T., Ikeda, K., Kumanishi, T. Br. J. Pharmacol. (2002) [Pubmed]
  3. Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. Marker, C.L., Stoffel, M., Wickman, K. J. Neurosci. (2004) [Pubmed]
  4. 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]
  5. Functional expression of an epitope-tagged G protein-coupled K+ channel (GIRK1). Philipson, L.H., Kuznetsov, A., Toth, P.T., Murphy, J.F., Szabo, G., Ma, G.H., Miller, R.J. J. Biol. Chem. (1995) [Pubmed]
  6. Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution. Nishida, M., MacKinnon, R. Cell (2002) [Pubmed]
  7. Ethanol opens G-protein-activated inwardly rectifying K+ channels. Kobayashi, T., Ikeda, K., Kojima, H., Niki, H., Yano, R., Yoshioka, T., Kumanishi, T. Nat. Neurosci. (1999) [Pubmed]
  8. 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]
  9. Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac). Kobayashi, T., Washiyama, K., Ikeda, K. Br. J. Pharmacol. (2003) [Pubmed]
  10. Structural characterization of the mouse Girk genes. Wickman, K., Pu, W.T., Clapham, D.E. Gene (2002) [Pubmed]
  11. Ts65Dn, a Mouse Model of Down Syndrome, Exhibits Increased GABAB-Induced Potassium Current. Best, T.K., Siarey, R.J., Galdzicki, Z. J. Neurophysiol. (2007) [Pubmed]
  12. 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]
  13. Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. Lesage, F., Guillemare, E., Fink, M., Duprat, F., Heurteaux, C., Fosset, M., Romey, G., Barhanin, J., Lazdunski, M. J. Biol. Chem. (1995) [Pubmed]
  14. Molecular and cellular diversity of neuronal G-protein-gated potassium channels. Koyrakh, L., Luján, R., Colón, J., Karschin, C., Kurachi, Y., Karschin, A., Wickman, K. J. Neurosci. (2005) [Pubmed]
  15. The weaver mouse gain-of-function phenotype of dopaminergic midbrain neurons is determined by coactivation of wvGirk2 and K-ATP channels. Liss, B., Neu, A., Roeper, J. J. Neurosci. (1999) [Pubmed]
  16. A region of the muscarinic-gated atrial K+ channel critical for activation by G protein beta gamma subunits. Takao, K., Yoshii, M., Kanda, A., Kokubun, S., Nukada, T. Neuron (1994) [Pubmed]
  17. Developmental expression of the GIRK family of inward rectifying potassium channels: implications for abnormalities in the weaver mutant mouse. Chen, S.C., Ehrhard, P., Goldowitz, D., Smeyne, R.J. Brain Res. (1997) [Pubmed]
  18. Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain. Lesage, F., Duprat, F., Fink, M., Guillemare, E., Coppola, T., Lazdunski, M., Hugnot, J.P. FEBS Lett. (1994) [Pubmed]
  19. 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]
  20. G-protein mediated gating of inward-rectifier K+ channels. Mark, M.D., Herlitze, S. Eur. J. Biochem. (2000) [Pubmed]
  21. Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. Marker, C.L., Luján, R., Loh, H.H., Wickman, K. J. Neurosci. (2005) [Pubmed]
  22. Molecular cloning of a mouse G-protein-activated K+ channel (mGIRK1) and distinct distributions of three GIRK (GIRK1, 2 and 3) mRNAs in mouse brain. Kobayashi, T., Ikeda, K., Ichikawa, T., Abe, S., Togashi, S., Kumanishi, T. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  23. A novel ubiquitously distributed isoform of GIRK2 (GIRK2B) enhances GIRK1 expression of the G-protein-gated K+ current in Xenopus oocytes. Isomoto, S., Kondo, C., Takahashi, N., Matsumoto, S., Yamada, M., Takumi, T., Horio, Y., Kurachi, Y. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  24. Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? Ikeda, K., Kobayashi, T., Kumanishi, T., Yano, R., Sora, I., Niki, H. Neurosci. Res. (2002) [Pubmed]
  25. Receptor-induced depletion of phosphatidylinositol 4,5-bisphosphate inhibits inwardly rectifying K+ channels in a receptor-specific manner. Cho, H., Lee, D., Lee, S.H., Ho, W.K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
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