Membrane impermeant antioestrogens discriminate between ligand- and voltage-gated cation channels in NG108-15 cells

Marcus Allen, Pamela A. Gale, Christy Hunter, Andrew Lloyd, Simon Hardy

Research output: Contribution to journalArticle

Abstract

Native 5-HT3 and AChR ligand-gated cation channels can be inhibited (blocked) by the non-steroidal antioestrogentamoxifen. However, the exact site and mechanism of inhibition by tamoxifen on these channels remain unclear. We haveinvestigated the action of the membrane impermeant quaternary derivative, ethylbromide tamoxifen (EBT), on native ligandgated5-HT3 receptor channels and voltage-gated K+ channels in NG108-15 cells using whole cell patch clamp. ExtracellularEBT inhibited whole cell cationic currents of 5-HT3 receptors with IC50 of 0.22 þ 0.4 WM (nH = 1.05 þ 0.2). The channel blockwas characterised by voltage independent and use independent behaviour (similar to that of tamoxifen). EBT was unable toinhibit voltage-gated K+ currents in NG108-15 cells. This was in contrast to the inhibition by tamoxifen which, at similarconcentrations, accelerated the apparent inactivation of these outward K+ currents. The inhibition of 5-HT3 receptors by amembrane impermeant derivative of tamoxifen supports the view that the binding site for antioestrogens is extracellular andthe inhibition is not mediated through genomic/transcriptional activity
Original languageEnglish
Pages (from-to)229-236
Number of pages8
JournalBBA - Biochimica et Biophysica Acta
Volume1509
Issue number1-2
DOIs
Publication statusPublished - 12 Dec 2000

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Estrogen Receptor Modulators
Tamoxifen
Cations
Ligands
Receptors, Serotonin, 5-HT3
Membranes
Ligand-Gated Ion Channels
Voltage-Gated Potassium Channels
Inhibitory Concentration 50
Binding Sites
ethylbromide tamoxifen

Keywords

  • 5-HT3 receptor
  • Tamoxifen
  • Ethylbromide tamoxifen
  • Potassium current

Cite this

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title = "Membrane impermeant antioestrogens discriminate between ligand- and voltage-gated cation channels in NG108-15 cells",
abstract = "Native 5-HT3 and AChR ligand-gated cation channels can be inhibited (blocked) by the non-steroidal antioestrogentamoxifen. However, the exact site and mechanism of inhibition by tamoxifen on these channels remain unclear. We haveinvestigated the action of the membrane impermeant quaternary derivative, ethylbromide tamoxifen (EBT), on native ligandgated5-HT3 receptor channels and voltage-gated K+ channels in NG108-15 cells using whole cell patch clamp. ExtracellularEBT inhibited whole cell cationic currents of 5-HT3 receptors with IC50 of 0.22 {\th} 0.4 WM (nH = 1.05 {\th} 0.2). The channel blockwas characterised by voltage independent and use independent behaviour (similar to that of tamoxifen). EBT was unable toinhibit voltage-gated K+ currents in NG108-15 cells. This was in contrast to the inhibition by tamoxifen which, at similarconcentrations, accelerated the apparent inactivation of these outward K+ currents. The inhibition of 5-HT3 receptors by amembrane impermeant derivative of tamoxifen supports the view that the binding site for antioestrogens is extracellular andthe inhibition is not mediated through genomic/transcriptional activity",
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Membrane impermeant antioestrogens discriminate between ligand- and voltage-gated cation channels in NG108-15 cells. / Allen, Marcus; Gale, Pamela A.; Hunter, Christy; Lloyd, Andrew; Hardy, Simon.

In: BBA - Biochimica et Biophysica Acta, Vol. 1509, No. 1-2, 12.12.2000, p. 229-236.

Research output: Contribution to journalArticle

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AU - Allen, Marcus

AU - Gale, Pamela A.

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AU - Lloyd, Andrew

AU - Hardy, Simon

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