Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Ethanol opens G-protein-activated inwardly rectifying K+ channels

Nature Neuroscience volume 2, pages 1091–1097 (1999)Cite this article

Abstract

Ethanol affects many functions of the brain and peripheral organs. 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. 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. Moreover, weaver mutant mice, which have a missense mutation in the GIRK2 channel, showed a loss of ethanol-induced analgesia. These results suggest that the GIRK channels in the brain and heart are important target sites for ethanol.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Effects of ethanol on GIRK and IRK channels.
Figure 2: Effects of a homologous series of n-alcohols on GIRK channels.
Figure 3: Effects of pertussis toxin (PTX) and antisense oligodeoxynucleotide (anti-Gβ1) against mRNA encoding the Xenopus oocyte Gβ1 subunit on ethanol-induced GIRK currents in oocytes co-expressing μ-opioid receptors and GIRK1 and GIRK2 subunits.
Figure 4: Activation of brain-type GIRK1/2 channels by ethanol in excised outside-out patches.
Figure 5: Ethanol-insensitive weaver GIRK2 channels.
Figure 6: Involvement of GIRK channels in ethanol-induced in-vivo effects.

Similar content being viewed by others

References

  1. Hobbs, W. R., Rall, T. W. & Verdoorn, T. A. in Goodman & Gilman's The Pharmacological Basis of Therapeutics 9th edn. (eds. Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W. & Gilman, A. F.) 361–396 (McGraw-Hill, New York, 1996).

    Google Scholar 

  2. Peoples, R. W., Li, C. & Weight, F. F. Lipid vs. protein theories of alcohol action in the nervous system. Annu. Rev. Pharmacol. Toxicol. 36, 185–201 (1996).

    Article  CAS  Google Scholar 

  3. Covernton, P. J. O. & Connolly, J. G. Differential modulation of rat neuronal nicotinic receptor subtypes by acute application of ethanol. Br. J. Pharmacol. 122, 1661– 1668 (1997).

    Article  CAS  Google Scholar 

  4. Mihic, S. J. et al. Sites of alcohol and volatile anaesthetic action on GABA A and glycine receptors. Nature 389, 385–389 (1997).

    Article  CAS  Google Scholar 

  5. Wick, M. J. et al. Mutations of γ-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor? Proc. Natl. Acad. Sci. USA 95, 6504–6509 (1998).

    Article  CAS  Google Scholar 

  6. Peoples, R. W. & Weight, F. F. Cutoff in potency implicates alcohol inhibition of N-methyl-D-aspartate receptors in alcohol intoxication. Proc. Natl. Acad. Sci. USA 92, 2825– 2829 (1995).

    Article  CAS  Google Scholar 

  7. Lovinger, D. M. & White, G. Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. Mol. Pharmacol. 40, 263–270 (1991).

    CAS  PubMed  Google Scholar 

  8. Li, C., Peoples, R. W. & Weight, F. F. Alcohol action on a neuronal membrane receptor: evidence for a direct interaction with the receptor protein. Proc. Natl. Acad. Sci. USA 91, 8200–8204 (1994).

    Article  CAS  Google Scholar 

  9. Treistman, S. N. et al. Effects of ethanol on calcium channels, potassium channels, and vasopressin release. Ann. NY. Acad. Sci. 625, 249–263 (1991).

    Article  CAS  Google Scholar 

  10. Covarrubias, M. & Rubin, E. Ethanol selectively blocks a noninactivating K+ current expressed in Xenopus oocytes. Proc. Natl. Acad. Sci. USA 90, 6957–6960 (1993).

    Article  CAS  Google Scholar 

  11. North, R. A. Drug receptors and the inhibition of nerve cells. Br. J. Pharmacol. 98, 13–28 ( 1989).

    Article  CAS  Google Scholar 

  12. Ikeda, K., Kobayashi, T., Ichikawa, T., Usui, H. & Kumanishi, T. Functional couplings of the δ- and the κ-opioid receptors with the G-protein-activated K+ channel. Biochem. Biophys. Res. Commun. 208, 302–308 (1995).

    Article  CAS  Google Scholar 

  13. Ikeda, K. et al. Comparison of the three mouse G-protein-activated K+ (GIRK) channels and functional couplings of the opioid receptors with the GIRK1 channel. Ann. NY. Acad. Sci. 801, 95–109 (1996).

    Article  CAS  Google Scholar 

  14. Ikeda, K. et al. Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K+ (GIRK) channel. Mol. Brain Res. 45, 117–126 ( 1997).

    Article  CAS  Google Scholar 

  15. Reuveny, E. et al. Activation of the cloned muscarinic potassium channel by G protein βγ subunits. Nature 370, 143–146 (1994).

    Article  CAS  Google Scholar 

  16. Brown, A. M. & Birnbaumer, L. Ionic channels and their regulation by G protein subunits. Annu. Rev. Physiol. 52, 197–213 (1990).

    Article  CAS  Google Scholar 

  17. Doupnik, C. A., Davidson, N. & Lester, H. A. The inward rectifier potassium channel family. Curr. Opin. Neurobiol. 5, 268–277 (1995).

    Article  CAS  Google Scholar 

  18. Kobayashi, T. et al. 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. Biochem. Biophys. Res. Commun. 208, 1166–1173 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Wickman, K., Seldin, M. F., Gendler, S. J. & Clapham, D. E. Partial structure, chromosome localization, and expression of the mouse Girk4 gene. Genomics 40, 395– 401 (1997).

    Article  CAS  Google Scholar 

  22. Karschin, C., Diβmann, E., Stuhmer, W. & Karschin, A. IRK(1–3) and GIRK(1–4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. J. Neurosci. 16, 3559–3570 ( 1996).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Lyon, R. C., McComb, J. A., Schreurs, J. & Goldstein, D. B. A relationship between alcohol intoxication and the disordering of brain membranes by a series of short-chain alcohols. J. Pharmacol. Exp. Ther. 218, 669–675 (1981).

    CAS  PubMed  Google Scholar 

  28. Yan, K. & Gautam, N. A domain on the G protein β subunit interacts with both adenylyl cyclase 2 and the muscarinic atrial potassium channel. J. Biol. Chem. 271, 17597– 17600 (1996).

    Article  CAS  Google Scholar 

  29. Devic, E. et al. The mRNA encoding a β subunit of heterotrimeric GTP-binding proteins is localized to the animal pole of Xenopus laevis oocyte and embryos. Mech. Dev. 59, 141– 151 (1996).

    Article  CAS  Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

  31. Osmanovic, S. S. & Shefner, S. A. Ethanol enhances inward rectification in rat locus ceruleus neurons by increasing the extracellular potassium concentration. J. Pharmacol. Exp. Ther. 271 , 334–342 (1994).

    CAS  PubMed  Google Scholar 

  32. Shefner, S. A. & Tabakoff, B. Basal firing rate of rat locus coeruleus neurons affects sensitivity to ethanol. Alcohol 2, 239–243 ( 1985).

    Article  CAS  Google Scholar 

  33. Carlen, P. L., Gurevich, N. & Durand, D. Ethanol in low doses augments calcium-mediated mechanisms measured intracellularly in hippocampal neurons. Science 215, 306–309 (1982).

    Article  CAS  Google Scholar 

  34. Lakhlani, P. P. et al. Substitution of a mutant α2a-adrenergic receptor via "hit and run" gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc. Natl. Acad. Sci. USA 94, 9950–9955 (1997).

    Article  CAS  Google Scholar 

  35. Penna, M., Brugere, S., Canas, M. & Saavedra, A. Cardiorespiratory reflex effects induced by intravenus administration of ethanol in rats. Alcohol 2, 603–609 ( 1985).

    Article  CAS  Google Scholar 

  36. Kobayashi, T., Ikeda, K. & Kumanishi, T. Effects of clozapine on the δ- and κ-opioid receptors and the G-protein-activated K+ (GIRK) channel expressed in Xenopus oocytes. Br. J. Pharmacol. 123, 421–426 (1998).

    Article  CAS  Google Scholar 

  37. Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Improved patch clamp techniques for high-resolution current recording from cells and cell free patches. Pflugers Arch. 391, 85–100 ( 1981).

    Article  CAS  Google Scholar 

  38. Ikeda, K. et al. Unique behavioural phenotypes of recombinant-inbred CXBK mice: Partial deficiency of sensitivity to μ- and κ-agonists. Neurosci. Res. 34, 149–155 (1999).

    Article  CAS  Google Scholar 

  39. Ikeda, K. et al. Reduced spontaneous activity of mice defective in the ε4 subunit of the NMDA receptor channel. Mol. Brain Res. 33, 61–71 (1995).

    Article  CAS  Google Scholar 

  40. Harris, R. A. et al. Mutant mice lacking the γ isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of γ-aminobutyrate type A receptors. Proc. Natl. Acad. Sci. USA 92, 3658–3662 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. G. Connolly and R. Kado for critical reading of the manuscript, K. Sakimura, K. Shimoji, Y. Ishihara, T. Someya and K. Baba for their cooperation and H. Kishida, N. Yamazaki, T. Ichikawa and K. Kobayashi for their assistance. This work was supported by a research grant from the Ministry of Education, Science, Sports and Culture of Japan, by the Cooperative Research Program of the RIKEN Brain Science Institute and in part by Research for the Future Program from the Japan Society for the Promotion of Science.

Author information

Authors and Affiliations

  1. Department of Molecular Neuropathology, Brain Research Institute, Niigata University, 1-757 Asahimachi, 951-8585, Niigata Niigata, Japan

    Toru Kobayashi & Toshiro Kumanishi

  2. Department of Psychiatry, Niigata University School of Medicine, Asahimachi, 951-8510, Niigata, Niigata, Japan

    Toru Kobayashi

  3. Laboratory for Neurobiology of Emotion, Brain Science Institute, RIKEN, Hirosawa, 351-0198, Wako, Saitama, Japan

    Kazutaka Ikeda & Hiroaki Niki

  4. Laboratory for Cellular Information Processing, Brain Science Institute, RIKEN, Hirosawa, 351-0198, Wako, Saitama, Japan

    Kazutaka Ikeda & Ryoji Yano

  5. Advanced Research Institute for Science and Engineering, Waseda University, Shinjuku, Tokyo, 169-8555, Japan

    Hiroshi Kojima & Tohru Yoshioka

  6. Department of Molecular Neurobiology, School of Human Sciences, Waseda University, Tokorozawa Saitama, 359-1164 , Japan

    Hiroshi Kojima & Tohru Yoshioka

Authors
  1. Toru Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazutaka Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroshi Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Niki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryoji Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tohru Yoshioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshiro Kumanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toru Kobayashi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kobayashi, T., Ikeda, K., Kojima, H. et al. Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat Neurosci 2, 1091–1097 (1999). https://doi.org/10.1038/16019

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/16019

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing