TY - JOUR
T1 - (Xeno)estrogen sensitivity of smooth muscle BK channels conferred by the regulatory β1 subunit
T2 - A study of β1 knockout mice
AU - Dick, Gregory M.
AU - Sanders, Kenton M.
PY - 2001/11/30
Y1 - 2001/11/30
N2 - Estrogen and xenoestrogens (i.e. agents that are not steroids but possess estrogenic activity) increase the open probability (Po) of large conductance Ca2+-activated K+ (BK) channels in smooth muscle. The mechanism of action may involve the regulatory β1 subunit. We used β1 subunit knockout (β1-/-) mice to test the hypothesis that the regulatory β1 subunit is essential for the activation of BK channels by tamoxifen, 4-OH tamoxifen (a major biologically active metabolite), and 17β-estradiol in native myocytes. Patch clamp recordings demonstrate BK channels from β1-/- mice were similar to wild type with the exception of markedly reduced Ca2+/voltage sensitivity and faster activation kinetics. In wild type myocytes, (xeno)estrogens increased NPo (Po × the number of channels, N), shifted the voltage of half-activation (V1/2) to more negative potentials, and decreased unitary conductance. These effects were non-genomic and direct, because they were rapid, reversible, and observed in cell-free patches. None of the (xeno)estrogens increased the NPo of BK channels from β1-/- mice, but all three agents decreased single channel conductance. Thus, (xeno)estrogens increase BK NPo through a mechanism involving the β1 subunit. The decrease in conductance did not require the β1 subunit and probably reflects an interaction with the pore-forming α subunit. We demonstrate regulation of smooth muscle BK channels by physiological (steroid hormones) and pharmacological (chemotherapeutic) agents and reveal the critical role of the β1 subunit in these responses in native myocytes.
AB - Estrogen and xenoestrogens (i.e. agents that are not steroids but possess estrogenic activity) increase the open probability (Po) of large conductance Ca2+-activated K+ (BK) channels in smooth muscle. The mechanism of action may involve the regulatory β1 subunit. We used β1 subunit knockout (β1-/-) mice to test the hypothesis that the regulatory β1 subunit is essential for the activation of BK channels by tamoxifen, 4-OH tamoxifen (a major biologically active metabolite), and 17β-estradiol in native myocytes. Patch clamp recordings demonstrate BK channels from β1-/- mice were similar to wild type with the exception of markedly reduced Ca2+/voltage sensitivity and faster activation kinetics. In wild type myocytes, (xeno)estrogens increased NPo (Po × the number of channels, N), shifted the voltage of half-activation (V1/2) to more negative potentials, and decreased unitary conductance. These effects were non-genomic and direct, because they were rapid, reversible, and observed in cell-free patches. None of the (xeno)estrogens increased the NPo of BK channels from β1-/- mice, but all three agents decreased single channel conductance. Thus, (xeno)estrogens increase BK NPo through a mechanism involving the β1 subunit. The decrease in conductance did not require the β1 subunit and probably reflects an interaction with the pore-forming α subunit. We demonstrate regulation of smooth muscle BK channels by physiological (steroid hormones) and pharmacological (chemotherapeutic) agents and reveal the critical role of the β1 subunit in these responses in native myocytes.
UR - http://www.scopus.com/inward/record.url?scp=0035977056&partnerID=8YFLogxK
U2 - 10.1074/jbc.M106851200
DO - 10.1074/jbc.M106851200
M3 - Article
C2 - 11590153
AN - SCOPUS:0035977056
SN - 0021-9258
VL - 276
SP - 44835
EP - 44840
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 48
ER -