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

Ohya, Susumu, Yukiko Kuwata, Kazuho Sakamoto, Katsuhiko Muraki, and Yuji Imaizumi. Cardioprotective effects of estradiol include the activation of large-conductance Ca -activated K channels in cardiac mitochondria. Am J Physiol Heart Circ Physiol 289: H1635–H1642, 2005; doi:10.1152/ajpheart.00016.2005.—The molecular components of the large-conductance Ca -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 Ca activated K channel 1-subunit (BK1) is substantially expressed in mammalian heart. A yeast two-hybrid assay showed the BK1 protein can interact with a mitochondrial protein, cytochrome c oxidase subunit I (Cco1). Results from immunocytochemical experiments also demonstrated that BK1 interacted with Cco1 and colocalized in rat cardiac mitochondria. Furthermore, 17 -estradiol, which enhances the activity of the BK channel -subunit only in the presence of the 1-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 17 -estradiol and blocked by paxilline. In combination, the present study revealed a new mechanism for the cardioprotective effects of 17 -estradiol, which include the activation of mitoKCa via the interaction with BK1. BK1 may be an important molecular component that functionally couples with both Cco1 and mitoKCa pore-forming -subunit.