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

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.

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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.

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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.

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Correspondence to Toru Kobayashi.

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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

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