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Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

Key Points

  • G protein-gated inwardly rectifying K+ (GIRK) channels hyperpolarize neurons, reducing membrane excitability. The basal activity of GIRK channels contributes to the resting potential of neurons, whereas activation of different G protein-coupled receptors (GPCRs) controls the excitability of neurons through GIRK-mediated neuronal self-inhibition (that is, the neurotransmitter released by a given neuron leads to inhibition of that neuron), neuron-to-neuron inhibition (that is, through a slow inhibitory postsynaptic potential) and network-level inhibition (that is, volume transmission).

  • High-resolution structures of cytoplasmic domains of GIRK channels provide a new 'toolbox' for investigating the molecular mechanisms underlying the gating and function of GIRK channels.

  • Brain slice electrophysiology provides several examples of plasticity in the slow IPSCs mediated by GIRK channels that are activated by GABAB (γ-aminobutyric acid type B) receptors and D2 dopamine receptors. In addition, activation of GIRK channels by adenosine is implicated in reversing long-term potentiation of glutamatergic transmission (depotentiation).

  • Studies on GIRK-knockout mice suggest GIRK channels are involved in pain perception mediated by endogenous pain modulators such as endorphins and endocannabinoids, and also analgesic drugs.

  • GIRK channels have also been implicated in the response to some drugs of abuse, including morphine, γ-hydroxybutyrate, amphetamines and ethanol, as well as some therapeutic drugs.

  • GIRK channels may contribute to the pathophysiology of several diseases, including epilepsy, addiction, Down's syndrome, ataxia and Parkinson's disease. Loss of GIRK function can lead to excessive neuronal excitability, contributing to epileptic seizures, whereas a gain of GIRK function can substantially reduce neural activity, as is postulated to occur in Down's syndrome.

Abstract

G protein-gated inwardly rectifying potassium (GIRK) channels hyperpolarize neurons in response to activation of many different G protein-coupled receptors and thus control the excitability of neurons through GIRK-mediated self-inhibition, slow synaptic potentials and volume transmission. GIRK channel function and trafficking are highly dependent on the channel subunit composition. Pharmacological investigations of GIRK channels and studies in animal models suggest that GIRK activity has an important role in physiological responses, including pain perception and memory modulation. Moreover, abnormal GIRK function has been implicated in altering neuronal excitability and cell death, which may be important in the pathophysiology of diseases such as epilepsy, Down's syndrome, Parkinson's disease and drug addiction. GIRK channels may therefore prove to be a valuable new therapeutic target.

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Figure 1: Physiology of GIRK channels in the mammalian brain.
Figure 2: Structural insights into gating and the formation of a macromolecular GIRK signalling complex.
Figure 3: Three types of neuronal signalling pathways for GIRK channels.
Figure 4: GIRK channels are implicated in various disease states.

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References

  1. Trevelyan, A. J. & Watkinson, O. Does inhibition balance excitation in neocortex? Prog. Biophys. Mol. Biol. 87, 109–143 (2005).

    PubMed  Google Scholar 

  2. Lujan, R., Maylie, J. & Adelman, J. P. New sites of action for GIRK and SK channels. Nature Rev. Neurosci. 10, 475–480 (2009).

    CAS  Google Scholar 

  3. Yamada, M., Inanobe, A. & Kurachi, Y. G protein regulation of potassium ion channels. Pharmacol. Rev. 50, 723–757 (1998).

    CAS  PubMed  Google Scholar 

  4. Pfaffinger, P. J., Martin, J. M., Hunter, D. D., Nathanson, N. M. & Hille, B. GTP-binding proteins couple cardiac muscarinic receptors to a K channel. Nature 317, 536–538 (1985).

    CAS  PubMed  Google Scholar 

  5. Logothetis, D. E., Kurachi, Y., Galper, J., Neer, E. J. & Clapham, D. E. The βγ subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature 325, 321–326 (1987).

    CAS  PubMed  Google Scholar 

  6. Wickman, K. D. et al. Recombinant G-protein βγ-subunits activate the muscarinic-gated atrial potassium channel. Nature 368, 255–257 (1994).

    CAS  PubMed  Google Scholar 

  7. Reuveny, E. et al. Activation of the cloned muscarinic potassium channel by G protein βγ subunits. Nature 370, 143–146 (1994). References 6 and 7 show that Gbg subunits activate GIRK channels, providing new evidence to resolve the G protein debate.

    CAS  PubMed  Google Scholar 

  8. Inanobe, A. et al. Gβγ directly binds to the carboxyl terminus of the G protein-gated muscarinic K+ channel, GIRK1. Biochem. Biophys. Res. Commun. 212, 1022–1028 (1995).

    CAS  PubMed  Google Scholar 

  9. Huang, C. L., Slesinger, P. A., Casey, P. J., Jan, Y. N. & Jan, L. Y. Evidence that direct binding of Gβγ to the GIRK1 G protein-gated inwardly rectifying K+ channel is important for channel activation. Neuron 15, 1133–1143 (1995).

    CAS  PubMed  Google Scholar 

  10. Wickman, K., Karschin, C., Karschin, A., Picciotto, M. R. & Clapham, D. E. Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4. J. Neurosci. 20, 5608–5615 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lesage, F. et al. Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J. Biol. Chem. 270, 28660–28667 (1995).

    CAS  PubMed  Google Scholar 

  12. Isomoto, S. et al. A novel ubiquitously distributed isoform of GIRK2 (GIRK2B) enhances GIRK1 expression of the G-protein-gated K+ current in Xenopus oocytes. Biochem. Biophys. Res. Commun. 218, 286–291 (1996).

    CAS  PubMed  Google Scholar 

  13. Inanobe, A. et al. Molecular cloning and characterization of a novel splicing variant of the Kir3.2 subunit predominantly expressed in mouse testis. J. Physiol. 521, 19–30 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lesage, F. et al. Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain. FEBS Lett. 353, 37–42 (1994).

    CAS  PubMed  Google Scholar 

  15. Wei, J. et al. Characterization of murine Girk2 transcript isoforms: structure and differential expression. Genomics 51, 379–390 (1998).

    CAS  PubMed  Google Scholar 

  16. Stoffel, M. et al. Cloning of rat KATP-2 channel and decreased expression in pancreatic islets of male Zucker diabetic fatty rats. Biochem. Biophys. Res. Commun. 212, 894–899 (1995).

    CAS  PubMed  Google Scholar 

  17. Bond, C. T. et al. Cloning and functional expression of the cDNA encoding an inwardly-rectifying potassium channel expressed in pancreatic β-cells and in the brain. FEBS Lett. 367, 61–66 (1995).

    CAS  PubMed  Google Scholar 

  18. Nelson, C. S., Marino, J. L. & Allen, C. N. Cloning and characterization of Kir3.1 (GIRK1) C-terminal alternative splice variants. Brain Res. Mol. Brain Res. 46, 185–196 (1997).

    CAS  PubMed  Google Scholar 

  19. Liao, Y. J., Jan, Y. N. & Jan, L. Y. Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain. J. Neurosci. 16, 7137–7150 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jelacic, T. M., Kennedy, M. E., Wickman, K. & Clapham, D. E. Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3. J. Biol. Chem. 275, 36211–36216 (2000).

    CAS  PubMed  Google Scholar 

  21. Tucker, S. J., Pessia, M. & Adelman, J. P. Muscarine-gated K+ channel: subunit stoichiometry and structural domains essential for G protein stimulation. Am. J. Physiol. 271, H379–H385 (1996).

    CAS  PubMed  Google Scholar 

  22. Slesinger, P. A. et al. Functional effects of the mouse weaver mutation on G protein-gated inwardly rectifying K+ channels. Neuron 16, 321–331 (1996).

    CAS  PubMed  Google Scholar 

  23. Kofuji, P., Davidson, N. & Lester, H. A. Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by Gβγ subunits and function as heteromultimers. Proc. Natl Acad. Sci. USA 92, 6542–6546 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Krapivinsky, G. et al. The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K+-channel proteins. Nature 374, 135–141 (1995).

    CAS  PubMed  Google Scholar 

  25. Jelacic, T. M., Sims, S. M. & Clapham, D. E. Functional expression and characterization of G-protein-gated inwardly rectifying K+ channels containing GIRK3. J. Membr. Biol. 169, 123–129 (1999).

    CAS  PubMed  Google Scholar 

  26. Labouèbe, G. et al. RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nature Neurosci. 12, 1559–1568 (2007). This paper shows that the 'club drug' GHB downregulates RGS2 in VTA dopaminergic neurons, which reduces the rewarding properties of GHB through altered GABA B –GIRK signalling.

    Google Scholar 

  27. Lüscher, C., Jan, L. Y., Stoffel, M., Malenka, R. C. & Nicoll, R. A. G-protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic, but not presynaptic transmitter actions in hippocampal neurons. Neuron 19, 687–695 (1997).

    PubMed  Google Scholar 

  28. Koyrakh, L. et al. Molecular and cellular diversity of neuronal G-protein-gated potassium channels. J. Neurosci. 25, 11468–11478 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Torrecilla, M. et al. G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons. J. Neurosci. 22, 4328–4334 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cruz, H. G. et al. Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice. J. Neurosci. 28, 4069–4077 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Marker, C. L., Lujan, R., Colon, J. & Wickman, K. Distinct populations of spinal cord lamina II interneurons expressing G-protein-gated potassium channels. J. Neurosci. 26, 12251–12259 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Slesinger, P. A., Stoffel, M., Jan, Y. N. & Jan, L. Y. Defective γ-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice. Proc. Natl Acad. Sci. USA 94, 12210–12217 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pravetoni, M. & Wickman, K. Behavioral characterization of mice lacking GIRK/Kir3 channel subunits. Genes Brain Behav. 7, 523–531 (2008).

    CAS  PubMed  Google Scholar 

  34. Kozell, L. B., Walter, N. A., Milner, L. C., Wickman, K. & Buck, K. J. Mapping a barbiturate withdrawal locus to a 0.44 Mb interval and analysis of a novel null mutant identify a role for Kcnj9 (GIRK3) in withdrawal from pentobarbital, zolpidem, and ethanol. J. Neurosci. 29, 11662–11673 (2009). This paper documents a search for genes in a quantitative trait locus associated with withdrawal. Mice containing a knockout of one these genes, Girk3 , exhibit less severe withdrawal from sedatives.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Morgan, A. D., Carroll, M. E., Loth, A. K., Stoffel, M. & Wickman, K. Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice. Neuropsychopharmacology 28, 932–938 (2003).

    CAS  PubMed  Google Scholar 

  36. Slesinger, P. A., Reuveny, E., Jan, Y. N. & Jan, L. Y. Identification of structural elements involved in G protein gating of the GIRK1 potassium channel. Neuron 15, 1145–1156 (1995).

    CAS  PubMed  Google Scholar 

  37. Nemec, J., Wickman, K. & Clapham, D. E. Gβγ binding increases the open time of IKACh: kinetic evidence for multiple Gβγ binding sites. Biophys. J. 76, 246–252 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ivanova-Nikolova, T. T. & Breitwieser, G. E. Effector contributions to Gβγ-mediated signaling as revealed by muscarinic potassium channel gating. J. Gen. Physiol. 109, 245–253 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ma, D. et al. Diverse trafficking patterns due to multiple traffic motifs in G protein-activated inwardly rectifying potassium channels from brain and heart. Neuron 33, 715–729 (2002).

    CAS  PubMed  Google Scholar 

  40. Lunn, M.-L. et al. A unique sorting nexin regulates trafficking of potassium channels via a PDZ domain interaction. Nature Neurosci. 10, 1249–1259 (2007).

    CAS  PubMed  Google Scholar 

  41. Inanobe, A. et al. Characterization of G-protein-gated K+ channels composed of Kir3.2 subunits in dopaminergic neurons of the substantia nigra. J. Neurosci. 19, 1006–1017 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nehring, R. B. et al. Neuronal inwardly rectifying K+ channels differentially couple to PDZ proteins of the PSD-95/SAP90 family. J. Neurosci. 20, 156–162 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cruz, H. G. et al. Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system. Nature Neurosci. 7, 153–159 (2004).

    CAS  PubMed  Google Scholar 

  44. Sui, J. L., Chan, K. W. & Logothetis, D. E. Na+ activation of the muscarinic K+ channel by a G-protein-independent mechanism. J. Gen. Physiol. 108, 381–391 (1996).

    CAS  PubMed  Google Scholar 

  45. Ho, I. H. & Murrell-Lagnado, R. D. Molecular determinants for sodium-dependent activation of G protein-gated K+ channels. J. Biol. Chem. 274, 8639–8648 (1999).

    CAS  PubMed  Google Scholar 

  46. Aryal, P., Dvir, H., Choe, S. & Slesinger, P. A. A discrete alcohol pocket involved in GIRK channel activation. Nature Neurosci. 12, 988–995 (2009).

    CAS  PubMed  Google Scholar 

  47. Kobayashi, T. et al. Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nature Neurosci. 2, 1091–1097 (1999).

    CAS  PubMed  Google Scholar 

  48. Lewohl, J. M. et al. G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nature Neurosci. 2, 1084–1090 (1999). References 46–48 show that alcohol activates GIRK channels through a discrete alcohol pocket in the channel.

    CAS  PubMed  Google Scholar 

  49. Mullner, C. et al. Heterologous facilitation of G protein-activated K+ channels by β-adrenergic stimulation via cAMP-dependent protein kinase. J. Gen. Physiol. 115, 547–558 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Medina, I. et al. A switch mechanism for Gβγ activation of IKACh . J. Biol. Chem. 275, 29709–29716 (2000).

    CAS  PubMed  Google Scholar 

  51. Sharon, D., Vorobiov, D. & Dascal, N. Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes. J. Gen. Physiol. 109, 477–490 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Stevens, E. B., Shah, B. S., Pinnock, R. D. & Lee, K. Bombesin receptors inhibit G protein-coupled inwardly rectifying K+ channels expressed in Xenopus oocytes through a protein kinase C-dependent pathway. Mol. Pharmacol. 55, 1020–1027 (1999).

    CAS  PubMed  Google Scholar 

  53. Leaney, J. L., Dekker, L. V. & Tinker, A. Regulation of a G protein-gated inwardly rectifying K+ channel by a Ca2+-independent protein kinase C. J. Physiol. 534, 367–379 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Mao, J. et al. Molecular basis for the inhibition of G protein-coupled inward rectifier K+ channels by protein kinase C. Proc. Natl Acad. Sci. USA 101, 1087–1092 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lei, Q., Talley, E. M. & Bayliss, D. A. Receptor-mediated inhibition of G protein-coupled inwardly rectifying potassium channels involves Gαq family subunits, phospholipase C, and a readily diffusable messenger. J. Biol. Chem. 276, 16720–16730 (2001).

    CAS  PubMed  Google Scholar 

  56. Sohn, J. W. et al. Receptor-specific inhibition of GABAB-activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus. J. Physiol. 580, 411–422 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Witkowski, G., Szulczyk, B., Rola, R. & Szulczyk, P. D1 dopaminergic control of G protein-dependent inward rectifier K+ (GIRK)-like channel current in pyramidal neurons of the medial prefrontal cortex. Neuroscience 155, 53–63 (2008).

    CAS  PubMed  Google Scholar 

  58. Lopes, C. M. et al. Alterations in conserved Kir channel–PIP2 interactions underlie channelopathies. Neuron 34, 933–944 (2002).

    CAS  PubMed  Google Scholar 

  59. Huang, C.-L., Feng, S. & Hilgemann, D. W. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ. Nature 391, 803–806 (1998).

    CAS  PubMed  Google Scholar 

  60. Zhang, H., He, C., Yan, X., Mirshahi, T. & Logothetis, D. E. Activation of inwardly rectifying K+ channels by distinct Ptdlns(4,5)P2 interactions. Nature Cell Biol. 1, 183–188 (1999).

    CAS  PubMed  Google Scholar 

  61. Kobrinsky, E., Mirshahi, T., Zhang, H., Jin, T. & Logothetis, D. E. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nature Cell Biol. 2, 507–514 (2000).

    CAS  PubMed  Google Scholar 

  62. Cho, H., Nam, G.-B., Lee, S. H., Earm, Y. E. & Ho, W.-K. Phosphatidylinositol 4,5-bisphosphate is acting as a signal molecule in α1-adrenergic pathway via the modulation of acetylcholine-activated K+ channels in mouse atrial myocytes. J. Biol. Chem. 276, 159–164 (2001).

    CAS  PubMed  Google Scholar 

  63. Meyer, T. et al. Depletion of phosphatidylinositol 4,5-bisphosphate by activation of phospholipase C-coupled receptors causes slow inhibition but not desensitization of G protein-gated inward rectifier K+ current in atrial myocytes. J. Biol. Chem. 276, 5650–5658 (2001).

    CAS  PubMed  Google Scholar 

  64. Nishida, M. & MacKinnon, R. Structural basis of inward rectification. Cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 Å resolution. Cell 111, 957–965 (2002).

    CAS  PubMed  Google Scholar 

  65. Pegan, S. et al. Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nature Neurosci. 8, 279–287 (2005).

    CAS  PubMed  Google Scholar 

  66. Inanobe, A., Matsuura, T., Nakagawa, A. & Kurachi, Y. Structural diversity in the cytoplasmic region of G protein-gated inward rectifier K+ channels. Channels 1, 39–45 (2007).

    PubMed  Google Scholar 

  67. Chang, H. K., Marton, L. J., Liang, K. K. & Shieh, R. C. K+ binding in the G-loop and water cavity facilitates Ba2+ movement in the Kir2.1 channel. Biochim. Biophys. Acta 1788, 500–506 (2009).

    CAS  PubMed  Google Scholar 

  68. Ma, D., Tang, X. D., Rogers, T. B. & Welling, P. A. An andersen-Tawil syndrome mutation in Kir2.1 (V302M) alters the G-loop cytoplasmic K+ conduction pathway. J. Biol. Chem. 282, 5781–5789 (2007).

    CAS  PubMed  Google Scholar 

  69. Tao, X., Avalos, J. L., Chen, J. & MacKinnon, R. Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 Å resolution. Science 326, 1668–1674 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Xu, Y., Shin, H.-G., Szep, S. & Lu, Z. Physical determinants of strong voltage sensitivity of K+ channel block. Nature Struct. Mol. Biol. 16, 1252–1258 (2009).

    CAS  Google Scholar 

  71. Pegan, S., Arrabit, C., Slesinger, P. A. & Choe, S. Andersen's syndrome mutation effects on the structure and assembly of the cytoplasmic domains of Kir2.1. Biochemistry 45, 8599–8606 (2006).

    CAS  PubMed  Google Scholar 

  72. Nishida, M., Cadene, M., Chait, B. T. & MacKinnon, R. Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J. 26, 4005–4015 (2007). This paper and references 64–66 provide the first set of high-resolution crystal structures of mammalian inwardly rectifying channels, giving a new toolbox for determining the molecular mechanisms that underlie channel gating.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kuo, A. et al. Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300, 1922–1926 (2003).

    CAS  PubMed  Google Scholar 

  74. Osawa, M. et al. Evidence for the direct interaction of spermine with the inwardly rectifying potassium channel. J. Biol. Chem. 284, 26117–26126 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kunkel, M. T. & Peralta, E. G. Identification of domains conferring G protein regulation on inward rectifier potassium channels. Cell 83, 443–449 (1995).

    CAS  PubMed  Google Scholar 

  76. Huang, C. L., Jan, Y. N. & Jan, L. Y. Binding of the G protein βγ subunit to multiple regions of G protein-gated inward-rectifying K+ channels. FEBS Lett. 405, 291–298 (1997).

    CAS  PubMed  Google Scholar 

  77. He, C., Zhang, H., Mirshahi, T. & Logothetis, D. E. Identification of a potassium channel site that interacts with G protein βγ subunits to mediate agonist-induced signaling. J. Biol. Chem. 274, 12517–12524 (1999).

    CAS  PubMed  Google Scholar 

  78. He, C. et al. Identification of critical residues controlling G protein-gated inwardly rectifying K+ channel activity through interactions with the βγ subunits of G proteins. J. Biol. Chem. 277, 6088–6096 (2002).

    CAS  PubMed  Google Scholar 

  79. Krapivinsky, G. et al. Gβγ binding to GIRK4 subunit is critical for G protein-gated K+ channel activation. J. Biol. Chem. 273, 16946–16952 (1998).

    CAS  PubMed  Google Scholar 

  80. Ivanina, T. et al.. Mapping the Gβγ-binding sites in GIRK1 and GIRK2 subunits of the G protein-activated K+ channel. J. Biol. Chem. 278, 29174–29183 (2003).

    CAS  PubMed  Google Scholar 

  81. Finley, M., Arrabit, C., Fowler, C., Suen, K. F. & Slesinger, P. A. βL-βM loop in the C-terminal domain of GIRK channels is important for Gβγ activation. J. Physiol. 555, 643–657 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Rubinstein, M. et al. Divergent regulation of GIRK1 and GIRK2 subunits of the neuronal G protein gated K+ channel by GαiGDP and Gβγ. J. Physiol. 587, 3473–3491 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kawano, T. et al. Interaction of Gαq and Kir3, G protein-coupled inwardly rectifying potassium channels. Mol. Pharmacol. 71, 1179–1184 (2007).

    CAS  PubMed  Google Scholar 

  84. Clancy, S. et al. Pertussis-toxin-sensitive Gα subunits selectively bind to C-terminal domain of neuronal GIRK channels: evidence for a heterotrimeric G-protein-channel complex. Mol. Cell. Neurosci. 28, 375–389 (2005).

    CAS  PubMed  Google Scholar 

  85. Peleg, S., Varon, D., Ivanina, T., Dessauer, C. W. & Dascal, N. Gαi controls the gating of the G protein-activated K+ channel, GIRK. Neuron 33, 87–99 (2002).

    CAS  PubMed  Google Scholar 

  86. Sarac, R. et al. Mutation of critical GIRK subunit residues disrupts N- and C-termini association and channel function. J. Neurosci. 25, 1836–1846 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Riven, I., Kalmanzon, E., Segev, L. & Reuveny, E. Conformational rearrangements associated with the gating of the G protein-coupled potassium channel revealed by FRET microscopy. Neuron 38, 225–235 (2003).

    CAS  PubMed  Google Scholar 

  88. Yi, B. A., Lin, Y., Jan, Y. N. & Jan, L. Y. Yeast screen for constitutively active mutant G protein-activated potassium channels. Neuron 29, 657–667 (2001).

    CAS  PubMed  Google Scholar 

  89. Sadja, R., Smadja, K., Alagem, N. & Reuveny, E. Coupling Gβγ-dependent activation to channel opening via pore elements in inwardly rectifying potassium channels. Neuron 29, 669–680 (2001).

    CAS  PubMed  Google Scholar 

  90. Jin, T. et al. The βγ subunits of G proteins gate a K+ channel by pivoted bending of a transmembrane segment. Mol. Cell 10, 469–481 (2002).

    CAS  PubMed  Google Scholar 

  91. Rosenhouse-Dantsker, A. et al. A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P2 . Nature Chem. Biol. 4, 624–631 (2008).

    CAS  Google Scholar 

  92. Riven, I., Iwanir, S. & Reuveny, E. GIRK channel activation involves a local rearrangement of a preformed G protein channel complex. Neuron 51, 561–573 (2006). In this paper, TIRF microscopy is used to investigate the interaction of G proteins with GIRK channels. The Gαβγ heterotrimer is shown to associate with the channel at rest, supporting the concept of a macromolecular signalling complex.

    CAS  PubMed  Google Scholar 

  93. David, M. et al. Interactions between GABA-B1 receptors and Kir3 inwardly rectifying potassium channels. Cell. Signal. 18, 2172–2181 (2006).

    CAS  PubMed  Google Scholar 

  94. Nobles, M., Benians, A. & Tinker, A. Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells. Proc. Natl Acad. Sci. USA 102, 18706–18711 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Nikolov, E. N. & Ivanova-Nikolova, T. T. Coordination of membrane excitability through a GIRK1 signaling complex in the atria. J. Biol. Chem. 279, 23630–23636 (2004).

    CAS  PubMed  Google Scholar 

  96. Lavine, N. et al. G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase. J. Biol. Chem. 277, 46010–46019 (2002).

    CAS  PubMed  Google Scholar 

  97. Lober, R. M., Pereira, M. A. & Lambert, N. A. Rapid activation of inwardly rectifying potassium channels by immobile G-protein-coupled receptors. J. Neurosci. 26, 12602–12608 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Schreibmayer, W. et al. Inhibition of an inwardly rectifying K+ channel by G-protein α-subunits. Nature 380, 624–627 (1996).

    CAS  PubMed  Google Scholar 

  99. Ivanina, T. et al. Gαi1 and Gαi3 differentially interact with, and regulate, the G protein-activated K+ channel. J. Biol. Chem. 279, 17260–17268 (2004).

    CAS  PubMed  Google Scholar 

  100. Geng, X. et al. Specificity of Gβγ signaling depends on Gα subunit coupling with G-protein-sensitive K channels. Pharmacology 84, 82–90 (2009). This study and references 84 and 85 show that PTX-sensitive Gα subunits alter GIRK function by interacting directly with the channel.

    CAS  PubMed  Google Scholar 

  101. Gales, C. et al. Real-time monitoring of receptor and G-protein interactions in living cells. Nature Methods 2, 177–184 (2005).

    CAS  PubMed  Google Scholar 

  102. Fowler, C. E., Aryal, P., Suen, K. F. & Slesinger, P. A. Evidence for association of GABAB receptors with Kir3 channels and RGS4 proteins. J. Physiol. 580, 51–65 (2007).

    CAS  PubMed  Google Scholar 

  103. Bünemann, M., Frank, M. & Lohse, M. J. Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc. Natl Acad. Sci. USA 100, 16077–16082 (2003).

    PubMed  PubMed Central  Google Scholar 

  104. Frank, M., Thumer, L., Lohse, M. J. & Bunemann, M. G protein activation without subunit dissociation depends on a Gαi-specific region. J. Biol. Chem. 280, 24584–24590 (2005).

    CAS  PubMed  Google Scholar 

  105. Digby, G. J., Sethi, P. R. & Lambert, N. A. Differential dissociation of G protein heterotrimers. J. Physiol. 586, 3325–3335 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Digby, G. J., Lober, R. M., Sethi, P. R. & Lambert, N. A. Some G protein heterotrimers physically dissociate in living cells. Proc. Natl Acad. Sci. USA 103, 17789–17794 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Gibson, S. K. & Gilman, A. G. Giα and Gβ subunits both define selectivity of G protein activation by α2-adrenergic receptors. Proc. Natl Acad. Sci. USA 103, 212–217 (2006).

    CAS  PubMed  Google Scholar 

  108. Clancy, S. M., Boyer, S. B. & Slesinger, P. A. Coregulation of natively expressed pertussis toxin-sensitive muscarinic receptors with G-protein-activated potassium channels. J. Neurosci. 27, 6388–6399 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Boyer, S. et al. Direct interaction of GABAB receptors with M2 muscarinic receptors enhances muscarinic signaling. J. Neurosci. 29, 15796–15809 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kulik, A. et al. Compartment-dependent colocalization of Kir3.2-containing K+ channels and GABAB receptors in hippocampal pyramidal cells. J. Neurosci. 26, 4289–4297 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chen, X. & Johnston, D. Constitutively active G-protein-gated inwardly rectifying K+ channels in dendrites of hippocampal CA1 pyramidal neurons. J. Neurosci. 25, 3787–3792 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Fernandez-Alacid, L. et al. Subcellular compartment-specific molecular diversity of pre- and post-synaptic GABA-activated GIRK channels in Purkinje cells. J. Neurochem. 110, 1363–1376 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Bacci, A., Huguenard, J. R. & Prince, D. A. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431, 312–316 (2004). This paper shows that low-threshold spiking interneurons undergo a hyperpolarization mediated by GIRK channels that surprisingly occurs cell-autonomously through endocannabinoids, providing an example of autaptic transmission involving GIRKs.

    CAS  PubMed  Google Scholar 

  114. Lacey, M. G., Mercuri, N. B. & North, R. A. Dopamine acts on D2 receptors to increase potassium conductance in neurones of the rat substantia nigra zona compacta. J. Physiol. 392, 397–416 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Newberry, N. R. & Nicoll, R. A. Comparison of the action of baclofen with gamma-aminobutyric acid on rat hippocampal pyramidal cells in vitro. J. Physiol. 360, 161–185 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Beckstead, M. J. & Williams, J. T. Long-term depression of a dopamine IPSC. J. Neurosci. 27, 2074–2080 (2007). This study reports that the dopamine-dependent slow IPSC is persistently reduced after strong dendrodendritic release of dopamine.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Dutar, P., Vu, H. M. & Perkel, D. J. Pharmacological characterization of an unusual mGluR-evoked neuronal hyperpolarization mediated by activation of GIRK channels. Neuropharmacology 38, 467–475 (1999).

    CAS  PubMed  Google Scholar 

  118. Nicoll, R. A. My close encounter with GABAB receptors. Biochem. Pharmacol. 68, 1667–1674 (2004).

    CAS  PubMed  Google Scholar 

  119. Scanziani, M. GABA spillover activates postsynaptic GABAB receptors to control rhythmic hippocampal activity. Neuron 25, 673–681 (2000).

    CAS  PubMed  Google Scholar 

  120. Isaacson, J. S., Solis, J. M. & Nicoll, R. A. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–175 (1993).

    CAS  PubMed  Google Scholar 

  121. Luscher, B. & Keller, C. A. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol. Ther. 102, 195–221 (2004).

    CAS  PubMed  Google Scholar 

  122. Beckstead, M. J., Grandy, D. K., Wickman, K. & Williams, J. T. Vesicular dopamine release elicits an inhibitory postsynaptic current in midbrain dopamine neurons. Neuron 42, 939–946 (2004).

    CAS  PubMed  Google Scholar 

  123. Jin, W. & Lu, Z. A novel high-affinity inhibitor for inward-rectifyier K+ channels. Biochemistry 37, 13291–13299 (1998).

    CAS  PubMed  Google Scholar 

  124. Michaeli, A. & Yaka, R. Dopamine inhibits GABAA currents in ventral tegmental area dopamine neurons via activation of presynaptic G-protein coupled inwardly-rectifying potassium channels. Neuroscience 165, 1159–1169 (2010). This paper provides evidence that GIRK channels contribute to a G protein-coupled, agonist-mediated presynaptic inhibition of transmitter release in the VTA.

    CAS  PubMed  Google Scholar 

  125. Ladera, C. et al. Pre-synaptic GABAB receptors inhibit glutamate release through GIRK channels in rat cerebral cortex. J. Neurochem. 107, 1506–1517 (2008).

    CAS  PubMed  Google Scholar 

  126. Sun, Q. Q., Huguenard, J. R. & Prince, D. A. Somatostatin inhibits thalamic network oscillations in vitro: actions on the GABAergic neurons of the reticular nucleus. J. Neurosci. 22, 5374–5386 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Pietersen, A. N., Lancaster, D. M., Patel, N., Hamilton, J. B. & Vreugdenhil, M. Modulation of gamma oscillations by endogenous adenosine through A1 and A2A receptors in the mouse hippocampus. Neuropharmacology 56, 481–492 (2009).

    CAS  PubMed  Google Scholar 

  128. Rice, M. E. & Cragg, S. J. Dopamine spillover after quantal release: rethinking dopamine transmission in the nigrostriatal pathway. Brain Res. Rev. 58, 303–313 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Huang, C. S. et al. Common molecular pathways mediate long-term potentiation of synaptic excitation and slow synaptic inhibition. Cell 123, 105–118 (2005). This paper shows that LTP of glutamatergic transmission leads to a concomitant potentiation of the GABA B –GIRK slow IPSC, thereby strengthening GABA-mediated inhibition.

    CAS  PubMed  Google Scholar 

  130. Chung, H. J., Qian, X., Ehlers, M., Jan, Y. N. & Jan, L. Y. Neuronal activity regulates phosphorylation-dependent surface delivery of G protein-activated inwardly rectifying potassium channels. Proc. Natl Acad. Sci. USA 106, 629–634 (2009).

    CAS  PubMed  Google Scholar 

  131. Chung, H. J. et al. G protein-activated inwardly rectifying potassium channels mediate depotentiation of long-term potentiation. Proc. Natl Acad. Sci. USA 106, 635–640 (2009). This paper provides evidence that adenosine-dependent reversal of glutamatergic LTP (depotentiation) involves activation of GIRK channels.

    CAS  PubMed  Google Scholar 

  132. Patil, N. et al. A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nature Genet. 11, 126–129 (1995).

    CAS  PubMed  Google Scholar 

  133. Kofuji, P. et al. Functional analysis of the weaver mutant GIRK2 K+ channel and rescue of weaver granule cells. Neuron 16, 941–952 (1996).

    CAS  PubMed  Google Scholar 

  134. Navarro, B. et al. Nonselective and Gβγ-insensitive weaver K+ channels. Science 272, 1950–1953 (1996).

    CAS  PubMed  Google Scholar 

  135. Ikeda, K., Kobayashi, T., Kumanishi, T., Niki, H. & Yano, R. Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia. Neurosci. Res. 38, 113–116 (2000).

    CAS  PubMed  Google Scholar 

  136. Roffler-Tarlov, S., Martin, B., Graybiel, A. M. & Kauer, J. S. Cell death in the midbrain of the murine mutation weaver. J. Neurosci. 16, 1819–1826 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Mitrovic, I. et al. Contribution of GIRK2-mediated postsynaptic signaling to opiate and α2-adrenergic analgesia and analgesic sex differences. Proc. Natl Acad. Sci. USA 100, 271–276 (2003).

    CAS  PubMed  Google Scholar 

  138. Blednov, Y. A., Stoffel, M., Alva, H. & Harris, R. A. A pervasive mechanism for analgesia: activation of GIRK2 channels. Proc. Natl Acad. Sci. USA 100, 277–282 (2003).

    CAS  PubMed  Google Scholar 

  139. Marker, C. L., Lujan, R., Loh, H. H. & Wickman, K. Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of μ- and δ- but not κ-opioids. J. Neurosci. 25, 3551–3559 (2005). This study and references 135, 137 and 138 implicate GIRK channels in the analgesic effects of opioids.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Ingram, S. L., Macey, T. A., Fossum, E. N. & Morgan, M. M. Tolerance to repeated morphine administration is associated with increased potency of opioid agonists. Neuropsychopharmacology 33, 2494–2450 (2008).

    CAS  PubMed  Google Scholar 

  141. Bradaïa, A., Berton, F., Ferrari, S. & Lüscher, C. β-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids. Proc. Natl Acad. Sci. USA 102, 3034–3039 (2005).

    PubMed  PubMed Central  Google Scholar 

  142. Dang, V. C., Napier, I. A. & Christie, M. J. Two distinct mechanisms mediate acute μ-opioid receptor desensitization in native neurons. J. Neurosci. 29, 3322–3327 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Whistler, J. L., Chuang, H.-H., Chu, P., Jan, L. Y. & von Zastrow, M. Functional dissociation of μ opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 23, 737–746 (1999).

    CAS  PubMed  Google Scholar 

  144. Ingram, S. L., Macey, T. A., Fossum, E. N. & Morgan, M. M. Tolerance to repeated morphine administration is associated with increased potency of opioid agonists. Neuropsychopharmacology 33, 2494–2504 (2007).

    PubMed  Google Scholar 

  145. Signorini, S., Liao, Y. J., Duncan, S. A., Jan, L. Y. & Stoffel, M. Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2. Proc. Natl Acad. Sci. USA 94, 923–927 (1997). This study is the first to use the GIRK-knockout mouse and shows that the loss of GIRK channels leads to spontaneous convulsions and a propensity for generalized seizures.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kobayashi, T., Washiyama, K. & Ikeda, K. Modulators of G protein-activated inwardly rectifying K+ channels: potentially therapeutic agents for addictive drug users. Ann. NY Acad. Sci. 1025, 590–594 (2004).

    CAS  PubMed  Google Scholar 

  147. Pei, Q., Lewis, L., Grahame-Smith, D. G. & Zetterstrom, T. S. C. Alteration in expression of G-protein-activated inward rectifier K+-channel subunits GIRK 1 and GIRK 2 in the rat brain following electroconvulsive shock. Neuroscience 90, 621–627 (1999).

    CAS  PubMed  Google Scholar 

  148. Mazarati, A. et al. 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. J. Pharmacol. Exp. Ther. 318, 700–708 (2006).

    CAS  PubMed  Google Scholar 

  149. Reeves, R. H. et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genet. 11, 177–184 (1995).

    CAS  PubMed  Google Scholar 

  150. Sago, H. et al. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc. Natl Acad. Sci. USA 95, 6256–6261 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Siarey, R. J. et al. Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology 38, 1917–1920 (1999).

    CAS  PubMed  Google Scholar 

  152. Luscher, C. & Ungless, M. A. The mechanistic classification of addictive drugs. PLoS Med. 3, e437 (2006).

    PubMed  PubMed Central  Google Scholar 

  153. Johnson, S. W. & North, R. A. Two types of neurone in the rat ventral tegmental area and their synaptic inputs. J. Physiol. 450, 455–468 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Szabo, B., Siemes, S. & Wallmichrath, I. Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur. J. Neurosci. 15, 2057–2061 (2002).

    PubMed  Google Scholar 

  155. Kajii, Y. et al. A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex. Mol. Psychiatry 8, 434–444 (2003).

    CAS  PubMed  Google Scholar 

  156. Federici, M., Nistico, R., Giustizieri, M., Bernardi, G. & Mercuri, N. B. Ethanol enhances GABAB-mediated inhibitory postsynaptic transmission on rat midbrain dopaminergic neurons by facilitating GIRK currents. Eur. J. Neurosci. 29, 1369–1377 (2009).

    PubMed  Google Scholar 

  157. Ikeda, K. et al. Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? Neurosci. Res. 44, 121–131 (2002).

    CAS  PubMed  Google Scholar 

  158. Hill, K. G., Alva, H., Blednov, Y. A. & Cunningham, C. L. Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice. Psychopharmacology (Berl.) 169, 108–114 (2003).

    CAS  Google Scholar 

  159. Bartoletti, M., Ricci, F. & Gaiardi, M. A GABAB agonist reverses the behavioral sensitization to morphine in rats. Psychoparmacology 192, 79–85 (2007).

    CAS  Google Scholar 

  160. Schein, J. C., Wang, J. K. & Roffler-Tarlov, S. K. The effect of GIRK2wv on neurite growth, protein expression, and viability in the CNS-derived neuronal cell line, CATH.A-differentiated. Neuroscience 134, 21–32 (2005).

    CAS  PubMed  Google Scholar 

  161. Harkins, A. B. & Fox, A. P. Cell death in weaver mouse cerebellum. Cerebellum 1, 201–206 (2002).

    PubMed  Google Scholar 

  162. Liss, B. et al. K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nature Neurosci. 8, 1742–1751 (2005).

    CAS  PubMed  Google Scholar 

  163. Patsoukis, N. et al. Thiol redox state and oxidative stress in midbrain and striatum of weaver mutant mice, a genetic model of nigrostriatal dopamine deficiency. Neurosci. Lett. 376, 24–28 (2005).

    CAS  PubMed  Google Scholar 

  164. Coulson, E. J. et al. p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate. J. Neurosci. 28, 315–324 (2008). This paper reports that activation of the nerve growth factor receptor leads to enhanced GIRK channel activity and generates a sustained K+ efflux that triggers apoptosis in dorsal root ganglion neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H. & Deisseroth, K. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025–1029 (2009).

    CAS  PubMed  Google Scholar 

  166. Soejima, M. & Noma, A. Mode of regulation of the ACh-sensitive K-channel by the muscarinic receptor in rabbit atrial cells. Pflügers Arch. 400, 424–431 (1984).

    CAS  PubMed  Google Scholar 

  167. Yatani, A. et al. The G protein-gated atrial K+ channel is stimulated by three distinct Giα-subunits. Nature 336, 680–682 (1988).

    CAS  PubMed  Google Scholar 

  168. Codina, J., Yatani, A., Grenet, D., Brown, A. M. & Birnbaumer, L. The α subunit of the GTP binding protein Gk opens atrial potassium channels. Science 236, 442–445 (1987).

    CAS  PubMed  Google Scholar 

  169. Leaney, J. L. & Tinker, A. The role of members of the pertussis toxin-sensitive family of G proteins in coupling receptors to the activation of the G protein-gated inwardly rectifying potassium channel. Proc. Natl Acad. Sci. USA 97, 5651–5656 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Hein, P., Frank, M., Hoffmann, C., Lohse, M. J. & Bunemann, M. Dynamics of receptor/G protein coupling in living cells. EMBO J. 24, 4106–4114 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Ippolito, D. L., Xu, M., Bruchas, M. R., Wickman, K. & Chavkin, C. Tyrosine phosphorylation of Kir3.1 in spinal cord is induced by acute inflammation, chronic neuropathic pain, and behavioral stress. J. Biol. Chem. 280, 41683–41693 (2005).

    CAS  PubMed  Google Scholar 

  172. Bettahi, I., Marker, C. L., Roman, M. I. & Wickman, K. Contribution of the Kir3.1 subunit to the muscarinic-gated atrial potassium channel IKACh. J. Biol. Chem. 277, 48282–48288 (2002).

    CAS  PubMed  Google Scholar 

  173. Blednov, Y. A., Stoffel, M., Chang, S. R. & Harris, R. A. GIRK2 deficient mice. Evidence for hyperactivity and reduced anxiety. Physiol. Behav. 74, 109–117 (2001).

    CAS  PubMed  Google Scholar 

  174. Blednov, Y. A., Stoffel, M., Chang, S. R. & Harris, R. A. Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice. J. Pharmacol. Exp. Ther. 298, 521–530 (2001).

    CAS  PubMed  Google Scholar 

  175. Wickman, K., Nemec, J., Gendler, S. J. & Clapham, D. E. Abnormal heart rate regulation in GIRK4 knockout mice. Neuron 20, 103–114 (1998).

    CAS  PubMed  Google Scholar 

  176. VanDongen, A. M. et al. Newly identified brain potassium channels gated by the guanine nucleotide binding protein Go . Science 242, 1433–1437 (1988).

    CAS  PubMed  Google Scholar 

  177. Leaney, J. L. Contribution of Kir3.1, Kir3.2A and Kir3.2C subunits to native G protein-gated inwardly rectifying potassium currents in cultured hippocampal neurons. Eur. J. Neurosci. 18, 2110–2118 (2003).

    PubMed  Google Scholar 

  178. Uchida, S., Akaike, N. & Nabekura, J. Dopamine activates inward rectifier K+ channel in acutely dissociated rat substantia nigra neurones. Neuropharmacology 39, 191–201 (2000).

    CAS  PubMed  Google Scholar 

  179. Grigg, J. J., Kozasa, T., Nakajima, Y. & Nakajima, S. Single-channel properties of a G-protein-coupled inward rectifier potassium channel in brain neurones. J. Neurophysiol. 75, 318–328 (1996).

    CAS  PubMed  Google Scholar 

  180. Miyake, M., Christie, M. J. & North, R. A. Single potassium channels opened by opioids in rat locus coeruleus neurons. Proc. Natl Acad. Sci. USA 86, 3419–3422 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Kawano, T., Zhao, P., Nakajima, S. & Nakajima, Y. Single-cell RT-PCR analysis of GIRK channels expressed in rat locus coeruleus and nucleus basalis neurons. Neurosci. Lett. 358, 63–67 (2004).

    CAS  PubMed  Google Scholar 

  182. Bajic, D., Koike, M., Albsoul-Younes, A. M., Nakajima, S. & Nakajima, Y. Two different inward rectifier K+ channels are effectors for transmitter-induced slow excitation in brain neurons. Proc. Natl Acad. Sci. USA 99, 14494–14499 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank P. Aryal for the three-dimensional structural figures and A. L. Lalive for compiling the Supplementary information table. Our work was support by McKnight Endowment Fund for Neuroscience (to P.A.S.), the Human Frontiers Science Foundation (to P.A.S. and C.L.), the NARSAD (to P.A.S.), the Swiss National Science Foundation (to C.L.), the National Institute of Neurological Disorders and Stroke (R01 NS37682; to P.A.S.) and the National Institute on Drug Abuse (R01 DA019022; to P.A.S. and C.L.). We apologize to our colleagues whose works could not be included owing to space limitations.

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Lüscher, C., Slesinger, P. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci 11, 301–315 (2010). https://doi.org/10.1038/nrn2834

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