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

Native 5-HT3 and AChR ligand-gated cation channels can be inhibited (blocke d) by the non-steroidal antioestrogen tamoxifen. However, the exact site an d mechanism of inhibition by tamoxifen on these channels remain unclear. We have investigated the action of the membrane impermeant quaternary derivat ive, ethylbromide tamoxifen (EBT), on native ligand-gated 5-HT3 receptor ch annels and voltage-gated K+ channels in NG108-15 cells using whole cell pat ch clamp. Extracellular EBT inhibited whole cell cationic currents of 5-HT3 receptors with IC50 of 0.22 +/- 0.4 muM (n(H) = 1.05 +/- 0.2). The channel block was characterised by voltage independent and use independent behavio ur (similar to that of tamoxifen). EBT was unable to inhibit voltage-gated K+ currents in NG108-15 cells. This was in contrast to the inhibition by ta moxifen which, at similar concentrations, accelerated the apparent inactiva tion of these outward K+ currents. The inhibition of 5-HT3 receptors by a m embrane impermeant derivative of tamoxifen supports the view that the bindi ng site for antioestrogens is extracellular and the inhibition is not media ted through genomic/transcriptional activity. (C) 2000 Elsevier Science B.V . All rights reserved.