Cardioprotective effects of estradiol include the activation of large-conductance Ca(2+)-activated K(+) channels in cardiac mitochondria.

The molecular components of the large-conductance Ca(2+)-activated K(+) channels that are functionally expressed in mitochondria (mitoK(Ca)) in cardiac myocytes have not been identified. Our experimental results show that the transcript corresponding to the large-conductance Ca(2+)-activated K(+) channel beta1-subunit (BK-beta1) is substantially expressed in mammalian heart. A yeast two-hybrid assay showed the BK-beta1 protein can interact with a mitochondrial protein, cytochrome c oxidase subunit I (Cco1). Results from immunocytochemical experiments also demonstrated that BK-beta1 interacted with Cco1 and colocalized in rat cardiac mitochondria. Furthermore, 17beta-estradiol, which enhances the activity of the BK channel alpha-subunit only in the presence of the beta1-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 mitoK(Ca), which had a conductance of approximately 270 pS, was enhanced by 17beta-estradiol and blocked by paxilline. In combination, the present study revealed a new mechanism for the cardioprotective effects of 17beta-estradiol, which include the activation of mitoK(Ca) via the interaction with BK-beta1. BK-beta1 may be an important molecular component that functionally couples with both Cco1 and mitoK(Ca) pore-forming alpha-subunit.