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

Abstract
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.
AuthorsSusumu Ohya, Yukiko Kuwata, Kazuho Sakamoto, Katsuhiko Muraki, Yuji Imaizumi
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 289 Issue 4 Pg. H1635-42 (Oct 2005) ISSN: 0363-6135 [Print] United States
PMID16113069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Flavoproteins
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Large-Conductance Calcium-Activated Potassium Channels
  • Potassium Channels, Calcium-Activated
  • Estradiol
Topics
  • Amino Acid Sequence
  • Animals
  • Estradiol (pharmacology)
  • Flavoproteins (metabolism)
  • Humans
  • In Vitro Techniques
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Large-Conductance Calcium-Activated Potassium Channels
  • Male
  • Mammals
  • Mice
  • Microscopy, Fluorescence
  • Mitochondria (drug effects, physiology)
  • Molecular Sequence Data
  • Myocardial Ischemia (physiopathology)
  • Myocytes, Cardiac (drug effects, physiology)
  • Potassium Channels, Calcium-Activated (genetics, physiology)
  • Rats
  • Rats, Wistar
  • Two-Hybrid System Techniques
  • Yeasts

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