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External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity

The mitochondrial large-conductance calcium-activated potassium channel (mitoBK(Ca)) is located in the inner mitochondrial membrane and seems to play a crucial role in cytoprotection. The mitoBK(Ca) channel is regulated by many modulators, including activators, such as calcium ions and inhibitors, s...

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Autores principales: Walewska, Agnieszka, Szewczyk, Adam, Koprowski, Piotr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657158/
https://www.ncbi.nlm.nih.gov/pubmed/36362175
http://dx.doi.org/10.3390/ijms232113391
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author Walewska, Agnieszka
Szewczyk, Adam
Koprowski, Piotr
author_facet Walewska, Agnieszka
Szewczyk, Adam
Koprowski, Piotr
author_sort Walewska, Agnieszka
collection PubMed
description The mitochondrial large-conductance calcium-activated potassium channel (mitoBK(Ca)) is located in the inner mitochondrial membrane and seems to play a crucial role in cytoprotection. The mitoBK(Ca) channel is regulated by many modulators, including activators, such as calcium ions and inhibitors, such as heme and its oxidized form hemin. Heme/hemin binds to the heme-binding motif (CXXCH) located between two RCK domains present in the mitochondrial matrix. In the present study, we used the patch-clamp technique in the outside-out configuration to record the activity of mitoBK(Ca) channels. This allowed for the application of channel modulators to the intermembrane-space side of the mitoBK(Ca). We found that hemin applied in this configuration inhibits the activity of mitoBK(Ca). In addition, we proved that the observed hemin effect is specific and it is not due to its interaction with the inner mitochondrial membrane. Our data suggest the existence of a new potential heme/hemin binding site in the structure of the mitoBK(Ca) channel located on the mitochondrial intermembrane space side, which could constitute a new way for the regulation of mitoBK(Ca) channel activity.
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spelling pubmed-96571582022-11-15 External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity Walewska, Agnieszka Szewczyk, Adam Koprowski, Piotr Int J Mol Sci Article The mitochondrial large-conductance calcium-activated potassium channel (mitoBK(Ca)) is located in the inner mitochondrial membrane and seems to play a crucial role in cytoprotection. The mitoBK(Ca) channel is regulated by many modulators, including activators, such as calcium ions and inhibitors, such as heme and its oxidized form hemin. Heme/hemin binds to the heme-binding motif (CXXCH) located between two RCK domains present in the mitochondrial matrix. In the present study, we used the patch-clamp technique in the outside-out configuration to record the activity of mitoBK(Ca) channels. This allowed for the application of channel modulators to the intermembrane-space side of the mitoBK(Ca). We found that hemin applied in this configuration inhibits the activity of mitoBK(Ca). In addition, we proved that the observed hemin effect is specific and it is not due to its interaction with the inner mitochondrial membrane. Our data suggest the existence of a new potential heme/hemin binding site in the structure of the mitoBK(Ca) channel located on the mitochondrial intermembrane space side, which could constitute a new way for the regulation of mitoBK(Ca) channel activity. MDPI 2022-11-02 /pmc/articles/PMC9657158/ /pubmed/36362175 http://dx.doi.org/10.3390/ijms232113391 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Walewska, Agnieszka
Szewczyk, Adam
Koprowski, Piotr
External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity
title External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity
title_full External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity
title_fullStr External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity
title_full_unstemmed External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity
title_short External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity
title_sort external hemin as an inhibitor of mitochondrial large-conductance calcium-activated potassium channel activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657158/
https://www.ncbi.nlm.nih.gov/pubmed/36362175
http://dx.doi.org/10.3390/ijms232113391
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AT koprowskipiotr externalheminasaninhibitorofmitochondriallargeconductancecalciumactivatedpotassiumchannelactivity