Encyclopedia of Signaling Molecules

Living Edition
| Editors: Sangdun Choi


  • Antonella Celluzzi
  • Andrea Masotti
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-6438-9_101534-1


Historical Background

In the last few years, the knowledge about the molecular and structural determinants of a special class of potassium channels regulated by G proteins, the G protein-activated inwardly rectifying K+ channels (GIRK channels) has increased (Luscher et al. 1997). GIRK channels are members of a large family of inwardly rectifying K+ channels (referred also with the symbols Kir1–Kir7), which stabilize the potential (by changing the current) to maintain the equilibrium potential for K+ (EK), corresponding to the zero current level. The term “inwardly rectifying K+ channels rectification” refers to the ability of these channels to pass current into the cells most efficiently when the cell is hyperpolarized, thus allowing a large influx of potassium ions. The mechanism behind this rectification, yet not fully understood, involves the blockade by high-affinity endogenous polyamines and Mg2+,which...


Down Syndrome Nicotine Dependence Contextual Fear Conditioning Down Syndrome Patient Galanin Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.


  1. Blednov YA, Stoffel M, Alva H, Harris RA. A pervasive mechanism for analgesia: activation of GIRK2 channels. Proc Natl Acad Sci U S A. 2003;100:277–82.CrossRefPubMedGoogle Scholar
  2. Blednov YA, Stoffel M, Chang SR, Harris RA. Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice. J Pharmacol Exp Ther. 2001;298:521–30.PubMedGoogle Scholar
  3. Bruehl S, Denton JS, Lonergan D, Koran ME, Chont M, Sobey C, et al. Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes. Pain. 2013;154:2853–9.CrossRefPubMedGoogle Scholar
  4. Ciruela F, Fernandez-Duenas V, Sahlholm K, Fernandez-Alacid L, Nicolau JC, Watanabe M, et al. Evidence for oligomerization between GABAB receptors and GIRK channels containing the GIRK1 and GIRK3 subunits. Eur J Neurosci. 2010;32:1265–77.CrossRefPubMedGoogle Scholar
  5. Clarke TK, Laucht M, Ridinger M, Wodarz N, Rietschel M, Maier W, et al. KCNJ6 is associated with adult alcohol dependence and involved in gene x early life stress interactions in adolescent alcohol drinking. Neuropsychopharmacology. 2011;36:1142–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cooper A, Grigoryan G, Guy-David L, Tsoory MM, Chen A, Reuveny E. Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice. Proc Natl Acad Sci U S A. 2012;109:2642–7.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Decher N, Renigunta V, Zuzarte M, Soom M, Heinemann SH, Timothy KW, et al. Impaired interaction between the slide helix and the C-terminus of Kir2.1: a novel mechanism of Andersen syndrome. Cardiovasc Res. 2007;75:748–57.CrossRefPubMedGoogle Scholar
  8. Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, et al. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003;60:1811–6.CrossRefPubMedGoogle Scholar
  9. Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998;280:69–77.CrossRefPubMedGoogle Scholar
  10. Duprat F, Lesage F, Guillemare E, Fink M, Hugnot JP, Bigay J, et al. Heterologous multimeric assembly is essential for K+ channel activity of neuronal and cardiac G-protein-activated inward rectifiers. Biochem Biophys Res Commun. 1995;212:657–63.CrossRefPubMedGoogle Scholar
  11. Fernandez-Alacid L, Aguado C, Ciruela F, Martin R, Colon J, Cabanero MJ, et al. Subcellular compartment-specific molecular diversity of pre- and post-synaptic GABA-activated GIRK channels in Purkinje cells. J Neurochem. 2009;110:1363–76.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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. 2000;38:113–6.CrossRefPubMedGoogle Scholar
  13. Isomoto S, Kondo C, Takahashi N, Matsumoto S, Yamada M, Takumi T, 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. 1996;218:286–91.CrossRefPubMedGoogle Scholar
  14. Itoi K, Sugimoto N. The brainstem noradrenergic systems in stress, anxiety and depression. J Neuroendocrinol. 2010;22:355–61.CrossRefPubMedGoogle Scholar
  15. Jelacic TM, Kennedy ME, Wickman K, Clapham DE. Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3. J Biol Chem. 2000;275:36211–6.CrossRefPubMedGoogle Scholar
  16. Lacey MG, Mercuri NB, North RA. Dopamine acts on D2 receptors to increase potassium conductance in neurones of the rat substantia nigra zona compacta. J Physiol. 1987;392:397–416.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lesage F, Guillemare E, Fink M, Duprat F, Heurteaux C, Fosset M, et al. Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J Biol Chem. 1995;270:28660–7.CrossRefPubMedGoogle Scholar
  18. Lesage F, Duprat F, Fink M, Guillemare E, Coppola T, Lazdunski M, et al. Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain. FEBS Lett. 1994;353:37–42.CrossRefPubMedGoogle Scholar
  19. Liao YJ, Jan YN, Jan LY. Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain. J Neurosci. 1996;16:7137–50.PubMedGoogle Scholar
  20. Lignon JM, Bichler Z, Hivert B, Gannier FE, Cosnay P, del Rio JA, et al. Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21. Physiol Genomics. 2008;33:230–9.CrossRefPubMedGoogle Scholar
  21. Llamosas N, Bruzos-Cidon C, Rodriguez JJ, Ugedo L, Torrecilla M. Deletion of GIRK2 Subunit of GIRK channels alters the 5-HT1A receptor-mediated signaling and results in a depression-resistant behavior. Int J Neuropsychopharmacol. 2015;18:pyv051.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Lujan R, de Velasco E MF, Aguado C, Wickman K. New insights into the therapeutic potential of Girk channels. Trends Neurosci. 2014;37:20–9.CrossRefPubMedGoogle Scholar
  23. Luscher B, Keller CA. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther. 2004;102:195–221.CrossRefPubMedGoogle Scholar
  24. Luscher C, Jan LY, Stoffel M, Malenka RC, Nicoll RA. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron. 1997;19:687–95.CrossRefPubMedGoogle Scholar
  25. Marker CL, Stoffel M, Wickman K. Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. J Neurosci. 2004;24:2806–12.CrossRefPubMedGoogle Scholar
  26. Marker CL, Cintora SC, Roman MI, Stoffel M, Wickman K. Hyperalgesia and blunted morphine analgesia in G protein-gated potassium channel subunit knockout mice. Neuroreport. 2002;13:2509–13.CrossRefPubMedGoogle Scholar
  27. Masotti A, Uva P, Davis-Keppen L, Basel-Vanagaite L, Cohen L, Pisaneschi E, et al. Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. Am J Hum Genet. 2015;96:295–300.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Nakatsuka T, Fujita T, Inoue K, Kumamoto E. Activation of GIRK channels in substantia gelatinosa neurones of the adult rat spinal cord: a possible involvement of somatostatin. J Physiol. 2008;586:2511–22.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Nishida M, Cadene M, Chait BT, MacKinnon R. Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J. 2007;26:4005–15.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Nishizawa D, Fukuda K, Kasai S, Ogai Y, Hasegawa J, Sato N, et al. Association between KCNJ6 (GIRK2) gene polymorphism rs2835859 and post-operative analgesia, pain sensitivity, and nicotine dependence. J Pharmacol Sci. 2014;126:253–63.CrossRefPubMedGoogle Scholar
  31. Nishizawa D, Nagashima M, Katoh R, Satoh Y, Tagami M, Kasai S, et al. Association between KCNJ6 (GIRK2) gene polymorphisms and postoperative analgesic requirements after major abdominal surgery. PLoS One. 2009;4:e7060.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Nockemann D, Rouault M, Labuz D, Hublitz P, McKnelly K, Reis FC, et al. The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Mol Med. 2013;5:1263–77.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell. 2001;105:511–9.CrossRefPubMedGoogle Scholar
  34. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9.CrossRefPubMedGoogle Scholar
  35. Toyoda A, Noguchi H, Taylor TD, Ito T, Pletcher MT, Sakaki Y, et al. Comparative genomic sequence analysis of the human chromosome 21 Down syndrome critical region. Genome Res. 2002;12:1323–32.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Whorton MR, MacKinnon R. Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium. Cell. 2011;147:199–208.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Williams JT, Colmers WF, Pan ZZ. Voltage- and ligand-activated inwardly rectifying currents in dorsal raphe neurons in vitro. J Neurosci. 1988;8:3499–506.PubMedGoogle Scholar
  38. Wiseman FK, Alford KA, Tybulewicz VL, Fisher EM. Down syndrome – recent progress and future prospects. Hum Mol Genet. 2009;18:R75–83.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Yamada M, Inanobe A, Kurachi Y. G protein regulation of potassium ion channels. Pharmacol Rev. 1998;50:723–60.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2016

Authors and Affiliations

  1. 1.Gene Expression – Microarrays LaboratoryBambino Gesù Children’s HospitalRomeItaly