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Inhibition of the cardiac Na+ channel Nav1.5 by carbon monoxide

Elies, J., Dallas, M. L., Boyle, J. P., Scragg, J. L., Duke, A., Steele, D. S. and Peers, C. (2014) Inhibition of the cardiac Na+ channel Nav1.5 by carbon monoxide. The Journal of Biological Chemistry, 289 (23). pp. 16421-16429. ISSN 1083-351X

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To link to this item DOI: 10.1074/jbc.M114.569996

Abstract/Summary

Sub-lethal 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 recognised CO-sensitive intracellular signalling pathways appeared to mediate CO inhibition of Nav1.5. Inhibition was, however, markedly suppressed by inhibition of nitric oxide (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 dithiothreitol 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 L-NAME, 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.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Centre for Integrative Neuroscience and Neurodynamics (CINN)
Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:36741
Uncontrolled Keywords:carbon monoxide; heart; Na+ channel; arrhythmia; patch-clamp
Publisher:American Society for Biochemistry and Molecular Biology

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