Tamoxifen activates smooth muscle BK channels through the regulatory β1 subunit

Estrogen (17β-estradiol; 17βE) and xenoestrogens, estrogenic compounds that are not steroid hormones, have non-genomic actions at plasma membrane receptors unrelated to the nuclear estrogen receptor. The open probability (Po) of large conductance Ca2+/voltage-sensitive k+(BK) channels is increased by 17βE through the regulatory β1 subunit. The pharmacological 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 Po in clinically relevant concentrations (0.1–10 μm). In whole cell patch clamp recordings on canine colonic myocytes, which express the β1 subunit, Tx activated charybdotoxin-sensitive K+current. In single channel experiments, Tx increased the NPo (Po × number channels; N) and decreased the unitary conductance (γ) of BK channels. Tx increased NPo (EC50 = 0.65 μm) in excised membrane patches independent of Ca2+ changes. The Tx mechanism of action requires the β1 subunit, as Tx increased the NPo of Slo α expressed in human embryonic kidney cells only in the presence of the β1 subunit. Tx decreased γ of the α subunit expressed alone, without effect on NPo. Our data indicate that Tx increases BK channel activity in therapeutic concentrations and reveal novel pharmacological properties attributable to the α and β1 subunits. These data shed light on BK channel structure and function, non-genomic mechanisms of regulation, and physiologically and therapeutically relevant effects of xenoestrogens.