Tamoxifen activates smooth muscle BK channels through the regulatory beta 1 subunit

Estrogen (17 beta -estradiol; 17 betaE) and xenoestrogens, estrogenic compo unds that are not steroid hormones, have nongenomic actions at plasma membr ane receptors unrelated to the nuclear estrogen receptor. The open probabil ity (P-o) of large conductance Ca2+/voltage-sensitive k(+)(BK) channels is increased by 17 betaE through the regulatory beta1 subunit. The pharmacolog ical nature of the putative membrane binding site is unclear. We probed the site by determining whether tamoxifen ((Z)-1-(p-dimethylaminoethoxy-phenyl )-1,2-diphenyl-1-butene; Tx), a chemotherapeutic xenoestrogen, increased P- o in clinically relevant concentrations (0.1-10 muM). In whole cell patch c lamp recordings on canine colonic myocytes, which express the beta1 subunit , Tx activated charybdotoxin-sensitive K+ current. In single channel experi ments, Tx increased the NPo (P-o x number channel; N) and decreased the uni tary conductance (gamma) of BK channels. Tx increased NPo (EC50 = 0.65 muM) in excised membrane patches independent of Ca2+ changes. The Tx mechanism of action requires the beta1 subunit, as Tx increased the NPo of Slo alpha expressed in human embryonic kidney cells only in the presence of the beta1 subunit. Tx decreased gamma of the alpha subunit expressed alone, without effect on NTPo. Our data indicate that Tx increases BK channel activity in therapeutic concentrations and reveal novel pharmacological properties attr ibutable to the a and beta1 subunits. These data shed light on BK channel s tructure and function, non-genomic mechanisms of regulation, and physiologi cally and therapeutically relevant effects of xenoestrogens.