Inhibition of G protein‐activated inwardly rectifying K + channels by fluoxetine (Prozac)

Inhibition of G protein‐activated inwardly rectifying K + channels by fluoxetine (Prozac) The effects of fluoxetine, a commonly used antidepressant drug, on G protein‐activated inwardly rectifying K+ channels (GIRK, Kir3) were investigated using Xenopus oocyte expression assays. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, fluoxetine reversibly reduced inward currents through the basal GIRK activity. The inhibition by fluoxetine showed a concentration‐dependence, a weak voltage‐dependence and a slight time‐dependence with a predominant effect on the instantaneous current elicited by voltage pulses and followed by slight further inhibition. Furthermore, in oocytes expressing GIRK1/2 channels and the cloned Xenopus A1 adenosine receptor, GIRK current responses activated by the receptor were inhibited by fluoxetine. In contrast, ROMK1 and IRK1 channels in other Kir channel subfamilies were insensitive to fluoxetine. The inhibitory effect on GIRK channels was not obtained by intracellularly applied fluoxetine, and not affected by extracellular pH, which changed the proportion of the uncharged to protonated fluoxetine, suggesting that fluoxetine inhibits GIRK channels from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of fluoxetine. We demonstrate that fluoxetine, at low micromolar concentrations, inhibits GIRK channels that play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate through activation of various G‐protein‐coupled receptors. The present results suggest that inhibition of GIRK channels by fluoxetine may contribute to some of its therapeutic effects and adverse side effects, particularly seizures in overdose, observed in clinical practice. British Journal of Pharmacology (2003) 138, 1119–1128. doi:10.1038/sj.bjp.0705172 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Inhibition of G protein‐activated inwardly rectifying K + channels by fluoxetine (Prozac)

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Publisher
Wiley
Copyright
2003 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0705172
pmid
12684268
Publisher site
See Article on Publisher Site

Abstract

The effects of fluoxetine, a commonly used antidepressant drug, on G protein‐activated inwardly rectifying K+ channels (GIRK, Kir3) were investigated using Xenopus oocyte expression assays. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, fluoxetine reversibly reduced inward currents through the basal GIRK activity. The inhibition by fluoxetine showed a concentration‐dependence, a weak voltage‐dependence and a slight time‐dependence with a predominant effect on the instantaneous current elicited by voltage pulses and followed by slight further inhibition. Furthermore, in oocytes expressing GIRK1/2 channels and the cloned Xenopus A1 adenosine receptor, GIRK current responses activated by the receptor were inhibited by fluoxetine. In contrast, ROMK1 and IRK1 channels in other Kir channel subfamilies were insensitive to fluoxetine. The inhibitory effect on GIRK channels was not obtained by intracellularly applied fluoxetine, and not affected by extracellular pH, which changed the proportion of the uncharged to protonated fluoxetine, suggesting that fluoxetine inhibits GIRK channels from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of fluoxetine. We demonstrate that fluoxetine, at low micromolar concentrations, inhibits GIRK channels that play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate through activation of various G‐protein‐coupled receptors. The present results suggest that inhibition of GIRK channels by fluoxetine may contribute to some of its therapeutic effects and adverse side effects, particularly seizures in overdose, observed in clinical practice. British Journal of Pharmacology (2003) 138, 1119–1128. doi:10.1038/sj.bjp.0705172

Journal

British Journal of PharmacologyWiley

Published: Mar 1, 2003

References

  • Ionic channels and their regulation by G protein subunits
    BROWN, BROWN; BIRNBAUMER, BIRNBAUMER
  • Signalling via the G protein‐activated K + channels
    DASCAL, DASCAL
  • Inhibition of voltage‐gated calcium channels by fluoxetine in rat hippocampal pyramidal cells
    DEÁK, DEÁK; LASZTOCZI, LASZTOCZI; PACHER, PACHER; PETHEO, PETHEO; KECSKEMETI, KECSKEMETI; SPAT, SPAT
  • The inward rectifier potassium channel family
    DOUPNIK, DOUPNIK; DAVIDSON, DAVIDSON; LESTER, LESTER
  • Inhibition of various antipsychotic drugs on the G‐protein‐activated inwardly rectifying K + (GIRK) channels expressed in Xenopus oocytes
    KOBAYASHI, KOBAYASHI; IKEDA, IKEDA; KUMANISHI, KUMANISHI
  • Functional characterization of an endogenous Xenopus oocyte adenosine receptor
    KOBAYASHI, KOBAYASHI; IKEDA, IKEDA; KUMANISHI, KUMANISHI
  • Block by fluoxetine of volume‐regulated anion channels
    MAERTENS, MAERTENS; WEI, WEI; VOETS, VOETS; DROOGMANS, DROOGMANS; NILIUS, NILIUS
  • Drug receptors and the inhibition of nerve cells
    NORTH, NORTH
  • Inwardly rectifying potassium channels
    REIMANN, REIMANN; ASHCROFT, ASHCROFT
  • Partial structure, chromosome localization, and expression of the mouse Girk4 gene
    WICKMAN, WICKMAN; SELDIN, SELDIN; GENDLER, GENDLER; CLAPHAM, CLAPHAM
  • Inhibition of neuronal K v potassium currents by the antidepressant drug, fluoxetine
    YEUNG, YEUNG; MILLAR, MILLAR; MATHIE, MATHIE

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