Cited by 90Cardiac Ischemia and ReperfusionMitochondrial Function and PathologyIon channel regulation and function

Potassium channel openers are uncoupling protonophores: implication in cardioprotection

Holmuhamedov, Ekhson L, Jahangir, Arshad, Oberlin, Andrew, Komarov, Alexander, Colombini, Marco, Terzic, Andre·2004·FEBS Letters

Abstract

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.

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Crossref · 10.1016/j.febslet.2004.05.031

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Authors
Holmuhamedov, E. L., Jahangir, A., Oberlin, A., Komarov, A., Colombini, M., & Terzic, A.
Affiliations
  • Mayo Clinic (US)
  • University of Maryland, College Park (US)
Venue
FEBS Letters
Publisher
Wiley
Published
2004-05-31
Volume
568
Issue
1-3
Pages
167-170
ISSN
  • 0014-5793 (ISSN-L)
  • 1873-3468
OpenAlex
W2086991052
Cited by
90
References
43
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 1 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 4
FWCI
8.09
Type
journal article
Language
en
Open access
closed
Locations
  • FEBS Letters (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (R01AG021201, AG-21201)
  • National Heart, Lung, and Blood Institute (HL64822, R01HL064822)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
potassium channel openers, mitochondrial uncoupling, protonophores, diazoxide, pinacidil, 2,4-dinitrophenol, mitochondrial membrane potential, mitochondrial respiration, oxidative phosphorylation, ischemic heart, cardioprotection, proton translocation, inner membrane permeability
MeSH terms
Animals, Cardiotonic Agents, Diazoxide, Mitochondria, Heart, Oxidative Phosphorylation, Uncoupling Agents, Potassium Channels, Pinacidil, Rats

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