Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species
Open accessAbstract
Conditions of stress, such as myocardial infarction, stimulate up-regulation of heme oxygenase (HO-1) to provide cardioprotection. Here, we show that CO, a product of heme catabolism by HO-1, directly inhibits native rat cardiomyocyte L-type Ca2+ currents and the recombinant alpha1C subunit of the human cardiac L-type Ca2+ channel. CO (applied via a recognized CO donor molecule or as the dissolved gas) caused reversible, voltage-independent channel inhibition, which was dependent on the presence of a spliced insert in the cytoplasmic C-terminal region of the channel. Sequential molecular dissection and point mutagenesis identified three key cysteine residues within the proximal 31 amino acids of the splice insert required for CO sensitivity. CO-mediated inhibition was independent of nitric oxide and protein kinase G but was prevented by antioxidants and the reducing agent, dithiothreitol. Inhibition of NADPH oxidase and xanthine oxidase did not affect the inhibitory actions of CO. Instead, inhibitors of complex III (but not complex I) of the mitochondrial electron transport chain and a mitochondrially targeted antioxidant (Mito Q) fully prevented the effects of CO. Our data indicate that the cardioprotective effects of HO-1 activity may be attributable to an inhibitory action of CO on cardiac L-type Ca2+ channels. Inhibition arises from the ability of CO to promote generation of reactive oxygen species from complex III of mitochondria. This in turn leads to redox modulation of any or all of three critical cysteine residues in the channel's cytoplasmic C-terminal tail, resulting in channel inhibition.
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Exposure to CO or a CO donor causes reversible inhibition of L-type Ca2+ channels in isolated rat myocytes.
“Thus, in isolated rat myocytes, exposure to CO or a CO donor causes reversible inhibition of L-type Ca2+ channels that could be replicated in HEK293 cells transfected with the α1C subunit of the human cardiac L-type Ca2+ channels containing a C-terminal splice variant.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [382]
CO-induced ROS derived from mitochondria inhibit L-type Ca2+ channel activity by a mechanism involving three Cys residues in the splice insertion region.
“Apparently, CO-induced ROS derived from mitochondria inhibit channel activity by a mechanism involving three Cys residues in the splice insertion region of this channel: mutation of any one of these Cys was sufficient to block CO's inhibitory effect.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [382]
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Redox regulation of mitochondrial function
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- Authors
- Scragg, J. L., Dallas, M. L., Wilkinson, J. A., Varadi, G., & Peers, C.
- Affiliations
- University of Leeds (GB)
- Corresponding author
- Scragg, Jason L.
- Peers, Chris
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 283
- Issue
- 36
- Pages
- 24412-24419
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3259849
- OpenAlex
- W2092562715
- Cited by
- 133
- References
- 43
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 15 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 10 · 2016: 7 · 2015: 11 · 2014: 10 · 2013: 8 · 2012: 12
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- British Heart Foundation
- University of Leeds
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- carbon monoxide, L-type calcium channels, heme oxygenase-1, cardiomyocytes, cysteine residues, redox modulation, reactive oxygen species, mitochondrial complex III, mitochondrial electron transport chain, channel inhibition, cardioprotection, NADPH oxidase, xanthine oxidase, antioxidants
- MeSH terms
- Animals, Carbon Monoxide, Cell Line, Heme Oxygenase (Decyclizing), Humans, Mitochondria, Heart, Myocardial Infarction, Nitric Oxide, Organophosphorus Compounds, Electron Transport Complex III, Ubiquinone, Xanthine Oxidase, Point Mutation, Reactive Oxygen Species, Protein Structure, Tertiary, Cyclic GMP-Dependent Protein Kinases, NADPH Oxidases, Calcium Channels, L-Type, Myocytes, Cardiac, Rats, Heme Oxygenase-1
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