Journal
FEBS LETTERS
Volume 568, Issue 1-3, Pages 167-170Publisher
WILEY
DOI: 10.1016/j.febslet.2004.05.031
Keywords
uncoupling; mitochondrion; diazoxide; pinacidil; cardioprotection; ischemia-reperfusion; heart
Funding
- NHLBI NIH HHS [HL64822] Funding Source: Medline
- NIA NIH HHS [R01 AG021201-02, AG21201, R01 AG021201] Funding Source: Medline
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Excessive build-up of mitochondrial protonic potential is harmful to cellular homeostasis, and modulation of inner membrane permeability a proposed countermeasure. Here, we demonstrate that structurally distinct potassium channel openers, diazoxide and pinacidil, facilitated transmembrane proton translocation generating H+-selective current through planar phospholipid membrane. Both openers depolarized mitochondria, activated state 4 respiration and reduced oxidative phosphorylation, recapitulating the signature of mitochondrial uncoupling. This effect was maintained in K+-free conditions and shared with the prototypic protonophore 2,4-dinitrophenol. Diazoxide, pinacidil and 2,4-dinitrophenol, but not 2,4-dinitrotoluene lacking protonophoric properties, preserved functional recovery of ischemic heart. The identified protonophoric property of potassium channel openers, thus, implicates a previously unrecognized component in their mechanism of cardioprotection. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.
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