Cardioprotective effects of estradiol include the activation of large-conductance Ca2+-activated K+ channels in cardiac mitochondria

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Abstract
The molecular components of the large-conductance Ca2+-activated K+ channels that are functionally expressed in mitochondria (mitoKCa) in cardiac myocytes have not been identified. Our experimental results show that the transcript corresponding to the large-conductance Ca2+-activated K+ channel β1-subunit (BK-β1) is substantially expressed in mammalian heart. A yeast two-hybrid assay showed the BK-β1 protein can interact with a mitochondrial protein, cytochrome c oxidase subunit I (Cco1). Results from immunocytochemical experiments also demonstrated that BK-β1 interacted with Cco1 and colocalized in rat cardiac mitochondria. Furthermore, 17β-estradiol, which enhances the activity of the BK channel α-subunit only in the presence of the β1-subunit, significantly increased flavoprotein oxidation in rat ventricle myocytes and decreased the rate of cell death under simulated ischemia. Single-channel recordings from mitochondrial inner membrane indicated that the activity of mitoKCa, which had a conductance of ∼270 pS, was enhanced by 17β-estradiol and blocked by paxilline. In combination, the present study revealed a new mechanism for the cardioprotective effects of 17β-estradiol, which include the activation of mitoKCa via the interaction with BK-β1. BK-β1 may be an important molecular component that functionally couples with both Cco1 and mitoKCa pore-forming α-subunit.