Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation

Zifan Pei, Yucheng Xiao, Jingwei Meng, Andy Hudmon and Theodore R. Cummins ()
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Zifan Pei: Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA
Yucheng Xiao: Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA
Jingwei Meng: Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA
Andy Hudmon: Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA
Theodore R. Cummins: Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Cardiac voltage-gated sodium channels (Nav1.5) play an essential role in regulating cardiac electric activity by initiating and propagating action potentials in the heart. Altered Nav1.5 function is associated with multiple cardiac diseases including long-QT3 and Brugada syndrome. Here, we show that Nav1.5 is subject to palmitoylation, a reversible post-translational lipid modification. Palmitoylation increases channel availability and late sodium current activity, leading to enhanced cardiac excitability and prolonged action potential duration. In contrast, blocking palmitoylation increases closed-state channel inactivation and reduces myocyte excitability. We identify four cysteines as possible Nav1.5 palmitoylation substrates. A mutation of one of these is associated with cardiac arrhythmia (C981F), induces a significant enhancement of channel closed-state inactivation and ablates sensitivity to depalmitoylation. Our data indicate that alterations in palmitoylation can substantially control Nav1.5 function and cardiac excitability and this form of post-translational modification is likely an important contributor to acquired and congenital arrhythmias.

Date: 2016
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DOI: 10.1038/ncomms12035

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