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

Estrogen (17beta-estradiol; 17betaE) 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 17betaE through the regulatory beta1 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 microm). In whole cell patch clamp recordings on canine colonic myocytes, which express the beta1 subunit, Tx activated charybdotoxin-sensitive K(+) current. In single channel experiments, Tx increased the NP(o) (P(o) x number channels; N) and decreased the unitary conductance (gamma) of BK channels. Tx increased NP(o) (EC(50) = 0.65 microm) in excised membrane patches independent of Ca(2+) changes. The Tx mechanism of action requires the beta1 subunit, as Tx increased the NP(o) 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 NP(o). Our data indicate that Tx increases BK channel activity in therapeutic concentrations and reveal novel pharmacological properties attributable to the alpha and beta1 subunits. These data shed light on BK channel structure and function, non-genomic mechanisms of regulation, and physiologically and therapeutically relevant effects of xenoestrogens.