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A Fluorescence-Based Assay of Membrane Potential for High-Throughput Functional Study of Two Endogenous Ion Channels in Two Epithelial Cell Lines
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Membrane impermeant antioestrogens discriminate between ligand- and voltage-gated cation channels in NG108-15 cells

M C Allen1, P A Gale, A C Hunter

  • 1School of Pharmacy and Biomolecular Sciences, University of Brighton, Lewes Road, BN2 4GJ, Brighton, UK.

Biochimica Et Biophysica Acta
|December 19, 2000
PubMed

Insights

Tamoxifen blocks serotonin 5-HT(3) receptor channels. Using a membrane-impermeant derivative, ethylbromide tamoxifen, researchers found the drug binds extracellularly to inhibit these channels, not through genomic activity.

Area of Science:

  • Neuropharmacology
  • Ion Channel Physiology

Background:

  • Tamoxifen, a non-steroidal antioestrogen, inhibits native 5-HT(3) and acetylcholine receptor (AChR) ligand-gated cation channels.
  • The precise site and mechanism of tamoxifen's channel inhibition remain incompletely understood.

Purpose of the Study:

  • To investigate the extracellular or intracellular site of tamoxifen's inhibitory action on ligand-gated ion channels.
  • To elucidate the mechanism of tamoxifen's inhibition on 5-HT(3) receptor channels and voltage-gated K(+) channels.

Main Methods:

  • Whole-cell patch clamp electrophysiology was employed on NG108-15 cells.
  • The effects of the membrane-impermeant tamoxifen derivative, ethylbromide tamoxifen (EBT), were assessed on native 5-HT(3) receptor and voltage-gated K(+) channels.

Main Results:

  • Extracellular EBT effectively inhibited 5-HT(3) receptor currents with an IC(50) of 0.22 μM, exhibiting voltage-independent and use-independent characteristics.
  • EBT did not inhibit voltage-gated K(+) currents, unlike tamoxifen, which accelerated their inactivation.
  • The findings support an extracellular binding site for tamoxifen on 5-HT(3) receptors.

Conclusions:

  • The inhibition of 5-HT(3) receptors by the membrane-impermeant EBT strongly suggests an extracellular binding site.
  • Tamoxifen's inhibition of 5-HT(3) receptors is not mediated through genomic or transcriptional mechanisms.
  • This study clarifies the mechanism of tamoxifen's interaction with specific ion channels.

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