The pure anti-oestrogen ICI 182,780 (Faslodex™) activates large conductance Ca 2+-activated K + channels in smooth muscle

Abstract

Oestrogen and tamoxifen activate large conductance Ca 2+-activated K + (BK Ca) channels in smooth muscle through a non-genomic mechanism that depends on the regulatory β1 subunit and an extracellular binding site. It is unknown whether a 'pure' anti-oestrogen such as ICI 182,780 (Faslodex™), that has no known oestrogenic properties, would have any effect on BK Ca channels. Using single channel patch clamp techniques on canine colonic myocytes, the hypothesis that ICI 182,780 would activate BK Ca channels was tested. ICI 182,780 increased the open probability of BK Ca channels in inside-out patches with an EC 50 of 1 μM. These data suggest that molecules with the ability to bind nuclear oestrogen receptors, regardless of oestrogenic or anti-oestrogenic nature, activate BK Ca channels through this nongenomic, membrane-delimited mechanism. The identity and characteristics of this putative binding site remain unclear; however, it has pharmacological similarity to oestrogen receptors α and β, as ICI 182,780 interacts with it.