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G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action

Abstract

G-protein-coupled inwardly rectifying potassium channels (GIRKs) are important for regulation of synaptic transmission and neuronal firing rates. Because of their key role in brain function, we asked if these potassium channels are targets of alcohol action. Ethanol enhanced function of cerebellar granule cell GIRKs coupled to GABAB receptors. Enhancement of GIRK function by ethanol was studied in detail using Xenopus oocytes expressing homomeric or heteromeric channels. Function of all GIRK channels was enhanced by intoxicating concentrations of ethanol, but other, related inwardly rectifying potassium channels were not affected. GIRK2/IRK1 chimeras and GIRK2 truncation mutants were used to identify a region of 43 amino acids in the carboxyl (C) terminus that is critical for the action of ethanol on these channels.

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Figure 1: Ethanol potentiates a potassium current induced by rapid activation of GABAB receptors in cerebellar granule cells in culture.
Figure 2: Ethanol enhances function of GIRK channels expressed in Xenopus oocytes.
Figure 3: Selective action of ethanol on GIRK, IRK and ROMK subunits expressed as homomeric or heteromeric channels in Xenopus oocytes.
Figure 4: (a) Current–voltage plot of changes in membrane conductance in response to extracellular potassium concentration.
Figure 5: Concentration–response curves for n-alcohols on the GIRK1/4 channel expressed in Xenopus oocytes.
Figure 6: Effect of 100 mM ethanol on wild-type GIRK2, IRK1, chimeras and truncation mutants.

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Acknowledgements

Supported by NIH grants AA06399, AA03527, GM47818 and AA11845.

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Correspondence to Joanne M. Lewohl.

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Lewohl, J., Wilson, W., Mayfield, R. et al. G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nat Neurosci 2, 1084–1090 (1999). https://doi.org/10.1038/16012

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