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Gene Review

Kcnj3  -  potassium channel, inwardly rectifying...

Rattus norvegicus

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

  • Molecular determinants for activation of G-protein-coupled inward rectifier K+ (GIRK) channels by extracellular acidosis [1].
  • 1. The contribution of endogenous regulators of G protein signalling (RGS) proteins to G protein modulated inwardly rectifying K(+) channel (GIRK) activation/deactivation was examined by expressing mutants of Galpha(oA) insensitive to both pertussis toxin (PTX) and RGS proteins in rat sympathetic neurons [2].
  • It is concluded that gabapentin is not an agonist at GABA(B) receptors that are functional in baclofen-induced antiallodynia in the postoperative pain model in vivo and in GIRK channel activation in ventrolateral PAG neurons in vitro [3].

Psychiatry related information on Kcnj3


High impact information on Kcnj3

  • Here we report that the same signaling pathway in the postsynaptic CA1 pyramidal neuron also causes LTP of the slow inhibitory postsynaptic current (sIPSC) mediated by metabotropic GABA(B) receptors (GABA(B)-Rs) and G protein-activated inwardly rectifying K(+) (GIRK) channels, both residing in dendritic spines as well as shafts [5].
  • It is now shown that IKACh is a heteromultimer of two distinct inwardly rectifying K(+)-channel subunits, GIRK1 and a newly cloned member of the family, CIR [6].
  • Based on sequence homology with cloned inwardly rectifying K+ channels, ROMK1 (ref. 11) and IRK1 (ref. 12), we have isolated a complementary DNA for a G-protein-coupled inwardly rectifying K+ channel (GIRK1) from rat heart [7].
  • In hippocampal neurons, expression of LGN, or LGN fragments that mimic or enhance LGN activity, hyperpolarizes the resting potential due to increased basal GIRK activity and reduces excitability [8].
  • Such rich trafficking behaviors provide a mechanism for dynamic regulation of GIRK channel density in the plasma membrane [9].

Chemical compound and disease context of Kcnj3

  • 3. NA-mediated activation of GIRK channels was abolished by pertussis toxin (PTX) pretreatment, indicating coupling via G proteins of the Gi/Go subfamily [10].
  • The peptides were administered alone or combined with an inhibitor of Gi protein pertussis toxin (PTX), Gi-protein activated K+ channels (GIRK) inhibitor tertiapin Q (TPQ), G(q/11) protein inhibitor [D-Arg1,D-Trp(5,7,9),Leu11]-substance P (dSP), or an inhibitor of intracellular Ca2+ release dantrolene [11].
  • SST, acting via sst(5) receptors and pertussis toxin-sensitive G-proteins, activated an inwardly rectifying K(+) (GIRK) current in 20 of 28 recorded cells to increase input conductance 15 +/- 3% above control and inhibited N-type Ca(2+) currents in 17 of 24 neurons via voltage-dependent mechanisms [12].

Biological context of Kcnj3

  • The point mutation I331R in the GIRK1 C terminus or L337R in the GIRK4 C terminus decreased the association between the N and C termini [13].
  • The hypothesis that similar channels play a role in neuronal inhibition is supported by the cloning of a nearly identical channel (KGB1) from a rat brain cDNA library [14].
  • Assignment of the gene encoding inwardly rectifying potassium channel, subfamily J, member 3 (Kcnj3) to rat chromosome 3q32 by in situ hybridization and radiation hybrid mapping [15].
  • These inhibitory effects are physiologically important in the voltage range between the resting membrane potential and the potential where voltage-gated Na+ and K+ currents are activated; that is where GIRK currents are outward [16].
  • Under current clamp, GIRK activation increased the cell membrane conductance by 1- to 2-fold, hyperpolarized the cell by 11-14 mV, and inhibited action potential firing by increasing the threshold current for firing by 2- to 3-fold [16].

Anatomical context of Kcnj3


Associations of Kcnj3 with chemical compounds

  • The expressed KGA channel is activated by serotonin 1A, muscarinic m2, and delta-opioid receptors via G proteins [14].
  • KGA is activated by guanosine 5'-[gamma-thio]triphosphate in excised patches, confirming activation by a membrane-delimited pathway, and displays a conductance equal to that of the endogenous channel in atrial cells [14].
  • Such activation was eliminated when a histidine residue in the M1-H5 linker was mutated to a non-titratable glutamine, i.e. H116Q in GIRK1 and H120Q in GIRK4 [1].
  • To investigate possible effects of adrenergic stimulation on G protein-activated inwardly rectifying K(+) channels (GIRK), acetylcholine (ACh)-evoked K(+) current, I(KACh), was recorded from adult rat atrial cardiomyocytes using the whole cell patch clamp method and a fast perfusion system [19].
  • Rf-evoked GIRK currents were not altered by PTX pretreatment but were suppressed by intracellularly injected guanosine-5'-(2-O-thio) diphosphate, a nonhydrolyzable GDP analog [20].

Physical interactions of Kcnj3


Regulatory relationships of Kcnj3


Other interactions of Kcnj3

  • Intracellular domain associations resulted in the coimmunoprecipitation of the GIRK1 N and C termini and GIRK4 N and C termini [13].
  • As heterotetramers, they comprise the GIRK1 and the GIRK2, -3, or -4 subunits [23].
  • These results indicate that Rf activates GIRK channel through an unidentified G protein-coupled receptor in rat brain and that this receptor can be cloned by the expression method demonstrated here [20].
  • 7. In summary, the attachment of GFP mutants to the N-terminus of G beta 1 or G gamma 2 does not qualitatively impair their ability to form a heterotrimer, modulate effectors (N-type Ca(2+) and GIRK channels), or couple to receptors [24].
  • The subcellular localization of GIRK1-IR in the Golgi apparatus of pyramidal cell somata and in the plasma membrane of dendrites and dendritic spines confirms the hypothesis that GIRK1 is synthesized by pyramidal cells and transported to the more distal dendritic processes [25].

Analytical, diagnostic and therapeutic context of Kcnj3

  • We have used in situ hybridization histochemistry to characterize the pattern of expression of GIRK1 mRNA in adult rat heart and brain [18].
  • Single-cell RT-PCR analysis of GIRK channels expressed in rat locus coeruleus and nucleus basalis neurons [26].
  • Whole-cell recordings of EPSCs and G-protein-activated inwardly rectifying (GIRK) currents were made from cultured hippocampal neurones to determine the effect of long-term agonist treatment on the presynaptic and postsynaptic responses mediated by GABA(B) receptors (GABA(B)Rs) [27].
  • 1. G protein-gated inwardly rectifying K+ (GIRK) channels were heterologously expressed in rat superior cervical ganglion (SCG) neurons by intranuclear microinjection [10].
  • 1. G protein-regulated inward rectifier K+ (GIRK) channels were over-expressed in dissociated rat superior cervical sympathetic (SCG) neurones by co-transfecting green fluorescent protein (GFP)-, GIRK1- and GIRK2-expressing plasmids using the biolistic technique [28].


  1. Molecular determinants for activation of G-protein-coupled inward rectifier K+ (GIRK) channels by extracellular acidosis. Mao, J., Li, L., McManus, M., Wu, J., Cui, N., Jiang, C. J. Biol. Chem. (2002) [Pubmed]
  2. Differential regulation of G protein-gated inwardly rectifying K(+) channel kinetics by distinct domains of RGS8. Jeong, S.W., Ikeda, S.R. J. Physiol. (Lond.) (2001) [Pubmed]
  3. Does gabapentin act as an agonist at native GABA(B) receptors? Cheng, J.K., Lee, S.Z., Yang, J.R., Wang, C.H., Liao, Y.Y., Chen, C.C., Chiou, L.C. J. Biomed. Sci. (2004) [Pubmed]
  4. Alteration in expression of G-protein-activated inward rectifier K+-channel subunits GIRK1 and GIRK2 in the rat brain following electroconvulsive shock. Pei, Q., Lewis, L., Grahame-Smith, D.G., Zetterström, T.S. Neuroscience (1999) [Pubmed]
  5. Common molecular pathways mediate long-term potentiation of synaptic excitation and slow synaptic inhibition. Huang, C.S., Shi, S.H., Ule, J., Ruggiu, M., Barker, L.A., Darnell, R.B., Jan, Y.N., Jan, L.Y. Cell (2005) [Pubmed]
  6. The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Krapivinsky, G., Gordon, E.A., Wickman, K., Velimirović, B., Krapivinsky, L., Clapham, D.E. Nature (1995) [Pubmed]
  7. Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel. Kubo, Y., Reuveny, E., Slesinger, P.A., Jan, Y.N., Jan, L.Y. Nature (1993) [Pubmed]
  8. Modulation of basal and receptor-induced GIRK potassium channel activity and neuronal excitability by the mammalian PINS homolog LGN. Wiser, O., Qian, X., Ehlers, M., Ja, W.W., Roberts, R.W., Reuveny, E., Jan, Y.N., Jan, L.Y. Neuron (2006) [Pubmed]
  9. 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]
  10. Heterologous expression and coupling of G protein-gated inwardly rectifying K+ channels in adult rat sympathetic neurons. Ruiz-Velasco, V., Ikeda, S.R. J. Physiol. (Lond.) (1998) [Pubmed]
  11. Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling. Mazarati, A., Lundström, L., Sollenberg, U., Shin, D., Langel, U., Sankar, R. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  12. Somatostatin inhibits thalamic network oscillations in vitro: actions on the GABAergic neurons of the reticular nucleus. Sun, Q.Q., Huguenard, J.R., Prince, D.A. J. Neurosci. (2002) [Pubmed]
  13. Mutation of critical GIRK subunit residues disrupts N- and C-termini association and channel function. Sarac, R., Hou, P., Hurley, K.M., Hriciste, D., Cohen, N.A., Nelson, D.J. J. Neurosci. (2005) [Pubmed]
  14. Atrial G protein-activated K+ channel: expression cloning and molecular properties. Dascal, N., Schreibmayer, W., Lim, N.F., Wang, W., Chavkin, C., DiMagno, L., Labarca, C., Kieffer, B.L., Gaveriaux-Ruff, C., Trollinger, D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  15. Assignment of the gene encoding inwardly rectifying potassium channel, subfamily J, member 3 (Kcnj3) to rat chromosome 3q32 by in situ hybridization and radiation hybrid mapping. Kreutz, R., Zürcher, H., Szpirer, J., Paul, M., Szpirer, C. Cytogenet. Cell Genet. (1999) [Pubmed]
  16. Activation of heteromeric G protein-gated inward rectifier K+ channels overexpressed by adenovirus gene transfer inhibits the excitability of hippocampal neurons. Ehrengruber, M.U., Doupnik, C.A., Xu, Y., Garvey, J., Jasek, M.C., Lester, H.A., Davidson, N. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  17. IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. Karschin, C., Dissmann, E., Stühmer, W., Karschin, A. J. Neurosci. (1996) [Pubmed]
  18. G protein-activated inwardly rectifying potassium channel (GIRK1/KGA) mRNA in adult rat heart and brain by in situ hybridization histochemistry. DePaoli, A.M., Bell, G.I., Stoffel, M. Mol. Cell. Neurosci. (1994) [Pubmed]
  19. Heterologous facilitation of G protein-activated K(+) channels by beta-adrenergic stimulation via cAMP-dependent protein kinase. Müllner, C., Vorobiov, D., Bera, A.K., Uezono, Y., Yakubovich, D., Frohnwieser-Steinecker, B., Dascal, N., Schreibmayer, W. J. Gen. Physiol. (2000) [Pubmed]
  20. Functional expression of a novel ginsenoside Rf binding protein from rat brain mRNA in Xenopus laevis oocytes. Choi, S., Jung, S.Y., Ko, Y.S., Koh, S.R., Rhim, H., Nah, S.Y. Mol. Pharmacol. (2002) [Pubmed]
  21. G-protein-gated inward rectifier K+ channel proteins (GIRK1) are present in the soma and dendrites as well as in nerve terminals of specific neurons in the brain. Ponce, A., Bueno, E., Kentros, C., Vega-Saenz de Miera, E., Chow, A., Hillman, D., Chen, S., Zhu, L., Wu, M.B., Wu, X., Rudy, B., Thornhill, W.B. J. Neurosci. (1996) [Pubmed]
  22. Coupling of rat somatostatin receptor subtypes to a G-protein gated inwardly rectifying potassium channel (GIRK1). Kreienkamp, H.J., Hönck, H.H., Richter, D. FEBS Lett. (1997) [Pubmed]
  23. A switch mechanism for G beta gamma activation of I(KACh). Medina, I., Krapivinsky, G., Arnold, S., Kovoor, P., Krapivinsky, L., Clapham, D.E. J. Biol. Chem. (2000) [Pubmed]
  24. Functional expression and FRET analysis of green fluorescent proteins fused to G-protein subunits in rat sympathetic neurons. Ruiz-Velasco, V., Ikeda, S.R. J. Physiol. (Lond.) (2001) [Pubmed]
  25. GIRK1 immunoreactivity is present predominantly in dendrites, dendritic spines, and somata in the CA1 region of the hippocampus. Drake, C.T., Bausch, S.B., Milner, T.A., Chavkin, C. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  26. Single-cell RT-PCR analysis of GIRK channels expressed in rat locus coeruleus and nucleus basalis neurons. Kawano, T., Zhao, P., Nakajima, S., Nakajima, Y. Neurosci. Lett. (2004) [Pubmed]
  27. GABA(B) receptor activation desensitizes postsynaptic GABA(B) and A(1) adenosine responses in rat hippocampal neurones. Wetherington, J.P., Lambert, N.A. J. Physiol. (Lond.) (2002) [Pubmed]
  28. Selective activation of heterologously expressed G protein-gated K+ channels by M2 muscarinic receptors in rat sympathetic neurones. Fernandez-Fernandez, J.M., Wanaverbecq, N., Halley, P., Caulfield, M.P., Brown, D.A. J. Physiol. (Lond.) (1999) [Pubmed]
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