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J. Biol. Chem., Vol. 276, Issue 48, 44835-44840, November 30, 2001
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From the Department of Physiology and Cell Biology, University of
Nevada School of Medicine, Reno, Nevada 89557
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
(Xeno)estrogen Sensitivity of Smooth Muscle BK Channels Conferred
by the Regulatory
1 Subunit
A STUDY OF 
1 KNOCKOUT MICE*
and1
subunit. We used 1 subunit knockout (1
/) mice to test the
hypothesis that the regulatory 1 subunit is essential for the
activation of BK channels by tamoxifen, 4-OH tamoxifen (a major
biologically active metabolite), and 17-estradiol in native
myocytes. Patch clamp recordings demonstrate BK channels from 1/
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 1/ mice, but all three agents decreased single
channel conductance. Thus, (xeno)estrogens increase BK NPo
through a mechanism involving the 1 subunit. The decrease in
conductance did not require the 1 subunit and probably reflects an
interaction with the pore-forming 
subunit. We demonstrate
regulation of smooth muscle BK channels by physiological (steroid
hormones) and pharmacological (chemotherapeutic) agents and reveal the
critical role of the 1 subunit in these responses in native myocytes.
*
This work was supported by National Institutes of Health
Grant DK41315.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of Postdoctoral National Research Service Award (F32
DK09947). To whom correspondence should be addressed: Dept. of
Physiology & Cell Biology, University of Nevada School of Medicine, Anderson Medical Bldg. 352, Reno, NV 89557. Tel.: 775-784-1293; Fax:
775-784-6903; E-mail: greg@physio.unr.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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