TY - JOUR
T1 - Tamoxifen Activates Smooth Muscle BK Channels through the Regulatory β1 Subunit
AU - Dick, Gregory M.
AU - Rossow, Charles F.
AU - Smirnov, Sergey
AU - Horowitz, Burton
AU - Sanders, Kenton M.
PY - 2001/9/14
Y1 - 2001/9/14
N2 - Estrogen (17β-estradiol; 17βE) and xenoestrogens, estrogenic compounds that are not steroid hormones, have nongenomic actions at plasma membrane receptors unrelated to the nuclear estrogen receptor. The open probability (Po) (P.) 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 NP o (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.
AB - Estrogen (17β-estradiol; 17βE) and xenoestrogens, estrogenic compounds that are not steroid hormones, have nongenomic actions at plasma membrane receptors unrelated to the nuclear estrogen receptor. The open probability (Po) (P.) 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 NP o (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.
UR - http://www.scopus.com/inward/record.url?scp=0035860731&partnerID=8YFLogxK
U2 - 10.1074/jbc.M104689200
DO - 10.1074/jbc.M104689200
M3 - Article
C2 - 11454866
AN - SCOPUS:0035860731
SN - 0021-9258
VL - 276
SP - 34594
EP - 34599
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -