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 (P o ) of large conductance Ca 2+ /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 P o in clinically relevant concentrations (0.1–10 μ m ). 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 NP o (P o × number channels; N) and decreased the unitary conductance (γ) of BK channels. Tx increased NP o (EC 50 = 0.65 μ m ) in excised membrane patches independent of Ca 2+ changes. The Tx mechanism of action requires the β1 subunit, as Tx increased the NP o 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 NP o . 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.