Calcium-dependent Nedd4-2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure
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Abstract
Aim
Reductions in voltage-gated sodium channel (Nav1.5) function/expression provide a slowed-conduction substrate for cardiac arrhythmias. Nedd4-2, which is activated by calcium, post-translationally modulates Nav1.5. We aim to investigate whether elevated intracellular calcium ([Ca
Methods
Using a combination of biochemical, electrophysiological, cellular and in vivo methods, we tested the effect and mechanism of calcium on Nedd4-2 and in turn Nav1.5.
Results
Increased [Ca
Conclusion
Calcium-mediated increases in Nedd4-2 downregulate Nav1.5 by ubiquitination. Nav1.5 is downregulated and co-localizes with Nedd4-2 and ubiquitin in failing rat heart. These data suggest a role of Nedd4-2 in Nav1.5 downregulation in HF.
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1748-1716