Targeting Mitochondrial Large-Conductance Calcium-Activated Potassium Channel by Hydrogen Sulfide via Heme-Binding Site
- 19 February 2022
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 381 (2), 137-150
- https://doi.org/10.1124/jpet.121.001017
Abstract
Reperfusion together with the preceding ischemic period results in serious damage to brain and heart tissues. Activation of potassium channels from the inner mitochondrial membrane leads to cytoprotection during such events. The mitochondrial large-conductance calcium-activated potassium channel (mitoBKCa) is one of these cytoprotective channels. It was previously shown that BKCa channels are blocked by hemin, which is present in excess during hemorrhage. In the experiments described in this work, we checked whether NaHS, known as a donor of gasotransmitter hydrogen sulfide (H2S), which can play an important role in cytoprotection, interacts with mitoBKCa channels. Indeed, using the biotin-switch method, it was found that mitoBKCa channels undergo S-sulfhydration in the presence of NaHS. Although patch-clamp experiments showed that NaHS has negligible effects on the activity of mitoBKCa channels, NaHS has been shown to almost fully activate hemin-inhibited mitoBKCa channels. The effects of NaHS were mimicked by imidazole, suggesting a common mechanism of activation of mitoBKCa channels inhibited by heme/hemin by molecules able to coordinate the iron ion of porphyrin. A set of absorption spectroscopy experiments with the 23 amino acid model peptides containing the heme-binding motif CXXCH suggested previously unrecognized roles of cysteines in heme binding. Significance Statement The activity of mitochondrial channels including mitoBKCa seems to play a significant role in cytoprotection during ischemia/reperfusion. Hemin, which is present in excess during hemorrhage, can potentially bind to and inhibit mitoBKCa activity. We found that hydrogen sulfide does not affect mitoBKCa activity unless it is blocked by hemin. In this case, hydrogen sulfide activates hemin-inhibited mitoBKCa by binding to hemin iron. The hydrogen sulfide effect could be mimicked in patch-clamp experiments by imidazole probably acting by a similar mechanism.This publication has 94 references indexed in Scilit:
- A Fluorescent Probe for Fast and Quantitative Detection of Hydrogen Sulfide in BloodAngewandte Chemie, 2011
- Hydrogen Sulfide and Hemeproteins: Knowledge and MysteriesAntioxidants and Redox Signaling, 2011
- Hydrogen sulfide attenuates cardiac dysfunction in a rat model of heart failure: a mechanism through cardiac mitochondrial protectionBioscience Reports, 2010
- BK channel activation: structural and functional insightsTrends in Neurosciences, 2010
- Identification of a Thiol/Disulfide Redox Switch in the Human BK Channel That Controls Its Affinity for Heme and COOnline Journal of Public Health Informatics, 2010
- A monobromobimane‐based assay to measure the pharmacokinetic profile of reactive sulphide species in bloodBritish Journal of Pharmacology, 2010
- H 2 S Signals Through Protein S-SulfhydrationScience Signaling, 2009
- Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial functionProceedings of the National Academy of Sciences of the United States of America, 2007
- The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel openerThe EMBO Journal, 2001
- Single channel recordings of Ca2+-activated K+ currents in rat muscle cell cultureNature, 1981