Al-Owais, MM, Hettiarachchi, NT, Boyle, JP orcid.org/0000-0001-5786-6559 et al. (6 more authors) (2017) Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K+ channel Kv1.5. Cell Death and Disease, 8. e3163. ISSN 2041-4889
Abstract
The voltage-gated K+ channel plays key roles in the vasculature and in atrial excitability, and contributes to apoptosis in various tissues. In this study, we have explored its regulation by carbon monoxide (CO), a product of the cytoprotective heme oxygenase enzymes, and a recognized toxin. CO inhibited recombinant Kv1.5 expressed in HEK293 cells in a concentration-dependent manner which involved multiple signalling pathways. CO inhibition was partially reversed by superoxide dismutase mimetics, and by suppression of mitochondrial reactive oxygen species. CO also elevated intracellular nitric oxide (NO) levels. Prevention of NO formation also partially reversed CO inhibition of Kv1.5, as did inhibition of soluble guanylyl cyclase. CO also elevated intracellular peroxynitrite levels, and a peroxynitrite scavenger markedly attenuated the ability of CO to inhibit Kv1.5. CO caused nitrosylation of Kv1.5, an effect which was also observed in C331A and C346A mutant forms of the channel, which had previously been suggested as nitrosylation sites within Kv1.5. Augmentation of Kv1.5 via exposure to hydrogen peroxide was fully reversed by CO. Native Kv1.5 recorded in HL-1 murine atrial cells was also inhibited by CO. Action potentials recorded in HL-1 cells were increased in amplitude and duration by CO, an effect mimicked and occluded by pharmacological inhibition of Kv1.5. Our data indicate that Kv1.5 is a target for modulation by CO via multiple mechanisms. This regulation has important implications for diverse cellular functions, including excitability, contractility and apoptosis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2017. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
Keywords: | potassium channel; carbon monoxide; nitric oxide; reactive oxygen species |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) > Academic Unit of Cardiovascular Medicine (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation PG/09/013/26885 British Heart Foundation PG/13/61/30410 |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Sep 2017 08:39 |
Last Modified: | 23 Jun 2023 22:36 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/cddis.2017.568 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:121526 |