Abstract
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 17alpha- or 17beta-estradiol. This effect was dose-dependent for 17beta-estradiol at concentrations ranging from 10 nm to 1 microm, while 17alpha-estradiol inhibited channel expression only at 1 microm. These effects were mediated by direct low affinity binding of estradiol to the maxi-K channel but not to its accessory beta1-subunit, as revealed by cell membrane estradiol binding assays. However, specific binding of estradiol to the channel was facilitated by the presence of the beta1 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 17alpha- and 17beta-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.
Highlights
Existing epidemiological data suggest a beneficial role for estrogens in maintaining cardiovascular protection in pre-menopausal women
Whole-cell recordings were performed in both HEK293 cell lines expressing the Maxi-K channels (maxi-K) channels either transiently or stably
A similar effect was observed with 17-estradiol with an attenuation of maxi-K channel current by ϳ38% at ϩ160 mV (Fig. 1D)
Summary
Existing epidemiological data suggest a beneficial role for estrogens in maintaining cardiovascular protection in pre-menopausal women. Whole-cell maxi-K channel currents and protein expression were attenuated by exposure to either 17␣- or 17-estradiol. 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.
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