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 M, while 17␣-estradiol inhibited channel expression only at 1 M. 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.Existing epidemiological data suggest a beneficial role for estrogens in maintaining cardiovascular protection in pre-menopausal women. However, other data show that estrogen-containing preparations can negatively affect the health of premenopausal as well as post-menopausal women (1-6). These results indicate the existence of complex estradiol-signaling mechanisms, possibly mediated by proteins other than classical intracellular estradiol receptors (7).One protein that has been hypothesized to be a potential effector of the action of estrogen is the large conductance Ca 2ϩ -and voltage-activated K ϩ channel (maxi-K channel). This channel provides a buffering repolarizing current in response to various physiological stimuli (8 -11). The mechanism by which estrogen interacts with this channel is unknown. However, both 17-estradiol and tamoxifen, a partial agonist of nuclear estradiol receptors, have been shown to activate maxi-K channels in both heterologous expression systems and smooth muscle cells, resulting in greater repolarizing currents (12, 13). Because acute incubation with either 17-estradiol or membrane-impermeable estrogen derivatives activate maxi-K channels, signal transduction pathways other than those mediated by classical nuclear estradiol receptors ␣ (ER␣) 1 or  (ER) are likely to be involved. Valverde et al. (14) showed that activation of maxi-K channels by 17-estradiol occurs when the channel is associated with its accessory 1-subunit. This effect was not observed in t...
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