The pure anti-oestrogen ICI 182,780 (Faslodex) activates large conductance Ca(2+)-activated K(+) channels in smooth muscle.
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 beta1 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 microM. 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 alpha and beta, as ICI 182,780 interacts with it.
Dick
Gregory M
GM
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, NV 89557, U.S.A. Greg@physio.unr.edu
D000818:Animals; D003106:Colon / Q000166:cytology; D004285:Dogs; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000077267:Fulvestrant; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
D004965:Estrogen Antagonists; D024681:Potassium Channels, Calcium-Activated; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol