First Author | Dick GM | Year | 2001 |
Journal | J Biol Chem | Volume | 276 |
Issue | 48 | Pages | 44835-40 |
PubMed ID | 11590153 | Mgi Jnum | J:72938 |
Mgi Id | MGI:2154020 | Doi | 10.1074/jbc.M106851200 |
Citation | Dick GM, et al. (2001) (Xeno)estrogen Sensitivity of Smooth Muscle BK Channels Conferred by the Regulatory beta 1 Subunit. A STUDY OF beta 1 KNOCKOUT MICE. J Biol Chem 276(48):44835-40 |
abstractText | Estrogen and xenoestrogens (i.e. agents that are not steroids but possess estrogenic activity) increase the open probability (P(o)) of large conductance Ca(2+)-activated K(+) (BK) channels in smooth muscle. The mechanism of action may involve the regulatory beta1 subunit. We used beta1 subunit knockout (beta1-/-) mice to test the hypothesis that the regulatory beta1 subunit is essential for the activation of BK channels by tamoxifen, 4-OH tamoxifen (a major biologically active metabolite), and 17beta-estradiol in native myocytes. Patch clamp recordings demonstrate BK channels from beta1-/- mice were similar to wild type with the exception of markedly reduced Ca(2+)/voltage sensitivity and faster activation kinetics. In wild type myocytes, (xeno)estrogens increased NP(o) (P(o) x the number of channels, N), shifted the voltage of half-activation (V(12)) 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 NP(o) of BK channels from beta1-/- mice, but all three agents decreased single channel conductance. Thus, (xeno)estrogens increase BK NP(o) through a mechanism involving the beta1 subunit. The decrease in conductance did not require the beta1 subunit and probably reflects an interaction with the pore-forming alpha subunit. We demonstrate regulation of smooth muscle BK channels by physiological (steroid hormones) and pharmacological (chemotherapeutic) agents and reveal the critical role of the beta1 subunit in these responses in native myocytes. |