Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species.

Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species. Research Abstract Details 

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Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species. Abstract Text:

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 Ca(2+) currents and the recombinant alpha(1C) subunit of the human cardiac L-type Ca(2+) 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 Ca(2+) 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.

Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species. Publishing Authors By Initials

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Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of biological chemistry

VOLUME: 283

Page Numbers: 24412-9

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 1

MONTH: 07

YEAR: 2008

Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

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Grant and Affiliation Information for Carbon Monoxide Inhibits L-type Ca2+ Channels via Redox Modulation of Key Cysteine Residues by Mitochondrial Reactive Oxygen Species.

AFFILIATION: Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of Genetics, Health, and Therapeutics, Level 10, Worsley Bldg., University of Leeds, Leeds LS2 9JT, United Kingdom and RMD Inc., Watertown, Massachusetts 02472.

Country: United States

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MEDLINETA: J Biol Chem

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