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J. Biol. Chem., Vol. 279, Issue 2, 1217-1223, January 9, 2004

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Estradiol Binding to Maxi-K Channels Induces Their Down-regulation via Proteasomal Degradation^*

Victoria P. Korovkina, Adam M. Brainard, Plabon Ismail, Thomas J. Schmidt, and Sarah K. England

From the Department of Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242

Estrogens exert their biological action via both genomic and non-genomic mechanisms. Proteins different from classical estradiol receptors are believed to mediate the latter effects. Here we demonstrate that the maxi-K channel functions as an estrogen-binding protein in transfected HEK293 cells. Whole-cell maxi-K channel currents and protein expression were attenuated by exposure to either 17- or 17-estradiol. This effect was dose-dependent for 17-estradiol at concentrations ranging from 10 nM to 1 µM, while 17-estradiol inhibited channel expression only at 1 µM. These effects were mediated by direct low affinity binding of estradiol to the maxi-K channel but not to its accessory 1-subunit, as revealed by cell membrane estradiol binding assays. However, specific binding of estradiol to the channel was facilitated by the presence of the 1 subunit. Addition of MG-132, a blocker of proteasomal degradation, stabilized channel expression. These data suggest that channel down-regulation is mediated by estrogen-induced proteasomal degradation, similar to the pathway used for estrogen receptor degradation. Membrane expression of endogenous maxi-K channels in cultured vascular smooth muscle cells was also attenuated by prolonged exposure to 17- and 17-estradiol. Thus our studies demonstrate that estrogen binds to maxi-K channels and may directly regulate channel expression and function. These results will have important implications in understanding estradiol-induced effects in multiple tissues including vascular smooth muscle.

Received for publication, August 18, 2003 , and in revised form, October 2, 2003.

^* This work was supported by the National Institutes of Health Grants R0137831 and K0201371 (to S. K. E.) and American Heart Association Grant 0120580Z (to V. P. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Physiology and Biophysics, 6-432 Bowen Science Bldg., University of Iowa, Carver College of Medicine, Iowa City, IA 52242. E-mail: sarah-england{at}uiowa.edu.

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