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Gene Review

Kcnj6  -  potassium inwardly-rectifying channel,...

Mus musculus

Synonyms: BIR1, G protein-activated inward rectifier potassium channel 2, GIRK-2, GIRK2, Girk2, ...
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Disease relevance of Kcnj6

  • Progressive neurodegenerative changes were associated with typical Parkinsonism in wv/wv mice [1].
  • We therefore predict that the normal human homolog of wv will be located on HSA 21 and would be in dosage imbalance in individuals with Down syndrome [2].
  • The resulting data indicate that the activation of GIRK2-containing potassium channels plays a significant role in hypothermia induced by the activation of serotonergic (5-HT(1A)), GABAergic (GABA(B)), muscarinic (m2), adenosine (A1), and mu, delta, and kappa opioid receptors [3].
  • Consistent with these findings, GIRK1 knock-out and GIRK2 knock-out mice exhibited hyperalgesia in the tail-flick test of thermal nociception [4].
  • In the light of normal pituitary hormone levels, normal hypothalamic monoamine concentrations and normal sex differences in gonadotropins, we conclude that the infertility in the male homozygote wv mouse lies within the tubule and is probably a primary defect in the germ cells [5].

Psychiatry related information on Kcnj6


High impact information on Kcnj6

  • This granule cell loss appears to be caused by a genetic defect in the pore region (Gly156-->Ser) of the heterotrimeric guanine nucleotide-binding protein (G protein)-gated inwardly rectifying potassium (K+) channel subunit (GIRK2) [8].
  • Neuronal differentiation rescued by implantation of Weaver granule cell precursors into wild-type cerebellar cortex [9].
  • In the cerebellum, adenosine receptors were absent in Weaver mice, which lack granule cells, and were displaced in Reeler mice, which have displacements of granule cells [10].
  • Moreover, weaver mutant mice, which have a missense mutation in the GIRK2 channel, showed a loss of ethanol-induced analgesia [11].
  • In addition, the GIRK2 channels play no role in the inhibition mediated by presynaptic G protein-coupled receptors, suggesting that the same receptor can couple to different effector systems according to its subcellular location in the neuron [12].

Chemical compound and disease context of Kcnj6


Biological context of Kcnj6

  • The pancreatic islet CIR and GIRK2 full-length cDNAs were cloned, and their genes were localized to human chromosomes 11q23-ter and 21, respectively [16].
  • CONCLUSIONS: Activation of the dopamine D(1)receptor in a stressful environment may be stronger in GIRK2 deficient mice, and this modified function of D(1) receptors may cause the transient hyperactive behavioral phenotype of these mice [6].
  • These results suggest that expression of the mutated channel is not a sufficient condition to induce cell death in the ventral mesencephalon of the wv/wv mice [17].
  • 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 [18].
  • The mechanism(s) by which a single amino acid substitution in GIRK2 protein leads to the severe phenotypes in the wv / wv mouse is not fully understood [18].

Anatomical context of Kcnj6

  • GIRK2 immunoreactivity is found in but not limited to brain regions known to be affected in wv mice, such as the cerebellar granule cells and dopaminergic neurons in the substantia nigra pars compacta [19].
  • We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus [20].
  • In the granuloprival weaver (wv/wv) cerebellum, hybridization signal is seen mainly in Purkinje cells [21].
  • Mesencephalic cell suspensions were prepared from E12 wild-type (+/+) mouse embryos and stereotaxically implanted into the dorsal neostriatum of weaver mutant mice (wv/wv), which have a genetic mesostriatal dopamine (DA) deficiency [22].
  • These results taken together indicate that DAT expression is one of the first targets in the ventral mesencephalon of the wv mutation, inducing a specific decrease of DA uptake in the striatum and the nucleus accumbens [23].

Associations of Kcnj6 with chemical compounds

  • Defective gamma-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice [24].
  • In a novel environment (open-field) only the highest dose of SKF 38393 used (20 mg/kg) produced significant activation, perhaps due to a ceiling effect in GIRK2 knockout mice [6].
  • The loss of GIRK1 or GIRK2 was correlated with equivalent, dramatic reductions in baclofen-evoked current in CA1 neurons [25].
  • The weaver mutation is a Gly-to-Ser substitution in a conserved region of the Girk2 G protein-coupled inward rectifying potassium channel [Patil N., Cox D. R., Bhat D., Faham M., Myers R. M. and Peterson A. S. (1995) Nature Genet. 11, 126-129] which induces early death of CGCs [26].
  • To evaluate other deficits, glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) were examined by autoradiography with [3H]MK-801 in 36 brain regions from heterozygous (wv/+) and homozygous (wv/wv) weaver mutants, and compared to wild type (+/+) mice [27].

Physical interactions of Kcnj6

  • We conclude that spinal G-protein-gated K+ channels consisting primarily of GIRK1/GIRK2 complexes modulate thermal nociception and mediate a significant component of the analgesia evoked by intrathecal administration of high morphine doses[4]
  • Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice [14].

Regulatory relationships of Kcnj6

  • However, GIRK3 chimeras with the amino- and carboxyl-terminal of GIRK2 are functionally expressed in the presence of GIRK1 [28].
  • The amplitude of the GABAB receptor-activated current was severely attenuated in granule cells isolated from both weaver and Girk2 null mutant mice [24].
  • To understand how the function of GIRK2 channels differs in these two mutant mice, we compared the G protein-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from Girk2 null mutant and weaver mutant mice with those from wild-type mice [24].
  • All GIRK2 splicing isoforms examined were expressed at higher levels in the Ts65Dn in comparison to the diploid hippocampus [29].

Other interactions of Kcnj6

  • In contrast, the expression of TH and VMAT2 mRNA remained unchanged in the wv/wv mice [23].
  • Hyperactivity and dopamine D1 receptor activation in mice lacking girk2 channels [6].
  • We also show that in contrast to wild-type neurons, all (wv/wv) dopaminergic SN neurons expressed calbindin, a calcium-binding protein that marks dopaminergic SN neurons resistant to neurodegeneration [30].
  • By contrast, the G protein-gated inwardly rectifying current and possibly the agonist-independent basal current appeared to be less selective for K+ ions in weaver but not Girk2 null mutant granule cells [24].
  • In the cerebella of two neurological granule cell-deficient mutants, weaver (wv) and staggerer (sg), parallin is not detected [31].

Analytical, diagnostic and therapeutic context of Kcnj6

  • 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 [16].
  • Furthermore, the activation of Kir3 channels containing the Kir3.2 subunit contributes to the analgesia evoked by a moderate dose of morphine [32].
  • We confirmed that acutely dissociated SN dopamine neurons indeed contain D3 and GIRK2 subunit mRNA using single-cell RT-PCR [33].
  • The phenotype of substantia nigra (SN) neurons in homozygous weaver (wv/wv) mice was studied by combining patch-clamp and single-cell RT-multiplex PCR techniques in midbrain slices of 14-d-old mice [30].
  • Levels of inhibitory amino acid receptors were studied in the weaver (wv/wv) mouse model of dopamine (DA) deficiency after unilateral intrastriatal transplantation of fetal mesencephalic cell suspensions [34].


  1. Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. Ebadi, M., Brown-Borg, H., El Refaey, H., Singh, B.B., Garrett, S., Shavali, S., Sharma, S.K. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  2. The mouse neurological mutant weaver maps within the region of chromosome 16 that is homologous to human chromosome 21. Reeves, R.H., Crowley, M.R., Lorenzon, N., Pavan, W.J., Smeyne, R.J., Goldowitz, D. Genomics (1989) [Pubmed]
  3. G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses. Costa, A.C., Stasko, M.R., Stoffel, M., Scott-McKean, J.J. J. Neurosci. (2005) [Pubmed]
  4. 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]
  5. Hypothalamic-pituitary-gonadal axis in the mutant weaver mouse. Schwartz, N.B., Szabo, M., Verina, T., Wei, J., Dlouhy, S.R., Won, L., Heller, A., Hodes, M.E., Ghetti, B. Neuroendocrinology (1998) [Pubmed]
  6. Hyperactivity and dopamine D1 receptor activation in mice lacking girk2 channels. Blednov, Y.A., Stoffel, M., Cooper, R., Wallace, D., Mane, N., Harris, R.A. Psychopharmacology (Berl.) (2002) [Pubmed]
  7. Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. Mitrovic, I., Margeta-Mitrovic, M., Bader, S., Stoffel, M., Jan, L.Y., Basbaum, A.I. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Nonselective and G betagamma-insensitive weaver K+ channels. Navarro, B., Kennedy, M.E., Velimirovíc, B., Bhat, D., Peterson, A.S., Clapham, D.E. Science (1996) [Pubmed]
  9. Neuronal differentiation rescued by implantation of Weaver granule cell precursors into wild-type cerebellar cortex. Gao, W.Q., Hatten, M.E. Science (1993) [Pubmed]
  10. Adenosine receptors: autoradiographic evidence for their location on axon terminals of excitatory neurons. Goodman, R.R., Kuhar, M.J., Hester, L., Snyder, S.H. Science (1983) [Pubmed]
  11. 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]
  12. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Lüscher, C., Jan, L.Y., Stoffel, M., Malenka, R.C., Nicoll, R.A. Neuron (1997) [Pubmed]
  13. Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice. Morgan, A.D., Carroll, M.E., Loth, A.K., Stoffel, M., Wickman, K. Neuropsychopharmacology (2003) [Pubmed]
  14. Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice. Blednov, Y.A., Stoffel, M., Chang, S.R., Harris, R.A. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  15. 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]
  16. 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]
  17. An immunocytochemical study of a G-protein-gated inward rectifier K+ channel (GIRK2) in the weaver mouse mesencephalon. Adelbrecht, C., Murer, M.G., Lauritzen, I., Lesage, F., Ladzunski, M., Agid, Y., Raisman-Vozari, R. Neuroreport (1997) [Pubmed]
  18. 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]
  19. Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain. Liao, Y.J., Jan, Y.N., Jan, L.Y. J. Neurosci. (1996) [Pubmed]
  20. 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]
  21. Cellular distribution of the RNA transcripts of a newly discovered gene in the brain of normal, weaver, Purkinje cell degeneration and reeler mutant mice as evidenced by in situ hybridization histochemistry. Kambouris, M., Sangameswaran, L., Dlouhy, S.R., Hodes, M.E., Ghetti, B., Triarhou, L.C. Brain Res. Mol. Brain Res. (1993) [Pubmed]
  22. Ventral mesencephalic grafts in the neostriatum of the weaver mutant mouse: structural molecule and receptor studies. Triarhou, L.C., Solà, C., Mengod, G., García-Ladona, F.J., Landwehrmeyer, B., Ghetti, B., Palacios, J.M. Cell transplantation. (1995) [Pubmed]
  23. Effect of the weaver mutation on the expression of dopamine membrane transporter, tyrosine hydroxylase and vesicular monoamine transporter in dopaminergic neurons of the substantia nigra and the ventral tegmental area. Adelbrecht, C., Agid, Y., Raisman-Vozari, R. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  24. Defective gamma-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice. Slesinger, P.A., Stoffel, M., Jan, Y.N., Jan, L.Y. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  25. 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]
  26. Weaver mutant mouse cerebellar granule cells respond normally to chronic depolarization. Bjerregaard, A., Mogensen, H.S., Hack, N., Balázs, R., Jørgensen, O.S. Int. J. Dev. Neurosci. (1997) [Pubmed]
  27. Distribution of glutamate receptors of the NMDA subtype in brains of heterozygous and homozygous weaver mutant mice. Reader, T.A., Sénécal, J. Neurochem. Res. (2001) [Pubmed]
  28. 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]
  29. Abnormal expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in hippocampus, frontal cortex, and substantia nigra of Ts65Dn mouse: a model of Down syndrome. Harashima, C., Jacobowitz, D.M., Witta, J., Borke, R.C., Best, T.K., Siarey, R.J., Galdzicki, Z. J. Comp. Neurol. (2006) [Pubmed]
  30. 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]
  31. Parallin, a cerebellar granule cell protein the expression of which is developmentally regulated by Purkinje cells: evidence from mutant mice. Smith, A.M., Mullen, R.J. Brain Res. Dev. Brain Res. (1997) [Pubmed]
  32. 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]
  33. D3 dopamine autoreceptors do not activate G-protein-gated inwardly rectifying potassium channel currents in substantia nigra dopamine neurons. Davila, V., Yan, Z., Craciun, L.C., Logothetis, D., Sulzer, D. J. Neurosci. (2003) [Pubmed]
  34. Partial restoration of striatal GABAA receptor balance by functional mesencephalic dopaminergic grafts in mice with hereditary parkinsonism. Stasi, K., Mitsacos, A., Giompres, P., Kouvelas, E.D., Triarhou, L.C. Exp. Neurol. (1999) [Pubmed]
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