Elies, J, Dallas, M, Boyle, JP et al. (4 more authors) (2014) Inhibition of the cardiac Na⁺ channel Nav1.5 by carbon monoxide. Journal of Biological Chemistry, 289 (23). 16421 - 16429. ISSN 0021-9258
Abstract
Sublethal carbon monoxide (CO) exposure is frequently associated with myocardial arrhythmias, and our recent studies have demonstrated that these may be attributable to modulation of cardiac Na(+) channels, causing an increase in the late current and an inhibition of the peak current. Using a recombinant expression system, we demonstrate that CO inhibits peak human Nav1.5 current amplitude without activation of the late Na(+) current observed in native tissue. Inhibition was associated with a hyperpolarizing shift in the steady-state inactivation properties of the channels and was unaffected by modification of channel gating induced by anemone toxin (rATX-II). Systematic pharmacological assessment indicated that no recognized CO-sensitive intracellular signaling pathways appeared to mediate CO inhibition of Nav1.5. Inhibition was, however, markedly suppressed by inhibition of NO formation, but NO donors did not mimic or occlude channel inhibition by CO, indicating that NO alone did not account for the actions of CO. Exposure of cells to DTT immediately before CO exposure also dramatically reduced the magnitude of current inhibition. Similarly, l-cysteine and N-ethylmaleimide significantly attenuated the inhibition caused by CO. In the presence of DTT and the NO inhibitor N(ω)-nitro-L-arginine methyl ester hydrochloride, the ability of CO to inhibit Nav1.5 was almost fully prevented. Our data indicate that inhibition of peak Na(+) current (which can lead to Brugada syndrome-like arrhythmias) occurs via a mechanism distinct from induction of the late current, requires NO formation, and is dependent on channel redox state.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article under the terms of the Creative Commons Attribution License. |
Keywords: | Arrhythmia; Carbon Monoxide; Heart; Nitric Oxide; Patch Clamp Electrophysiology; Sodium Channels; Carbon Monoxide; HEK293 Cells; Humans; NAV1.5 Voltage-Gated Sodium Channel; Oxidation-Reduction |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute of Membrane and Systems Biology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 May 2015 13:24 |
Last Modified: | 17 Jan 2018 15:23 |
Published Version: | http://dx.doi.org/10.1074/jbc.M114.569996 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Identification Number: | 10.1074/jbc.M114.569996 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:84443 |