Potassium channel openers are uncoupling protonophores: Implication in cardioprotection

Ekhson L. Holmuhamedov, Arshad Jahangir, Andrew Oberlin, Alexander Komarov, Marco Colombini, Andre Terzic

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)167-170
Number of pages4
JournalFEBS Letters
Issue number1-3
StatePublished - Jun 18 2004


  • Cardioprotection
  • Diazoxide
  • Heart
  • Ischemia-reperfusion
  • Mitochondrion
  • Pinacidil
  • Uncoupling

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology


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