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

Zifan Pei,Andy Hudmon,Theodore R Cummins,Yucheng Xiao,Jingwei Meng

doi:10.1038/ncomms12035

Zifan Pei, Andy Hudmon + Show 3 more

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https://doi.org/10.1038/ncomms12035

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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.

Highlights

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
A previously identified disease mutation in Nav1.5 associated with cardiac arrhythmia illustrates how the potential loss of palmitoylation at this crucial residue alters channel inactivation and dysregulates myocyte excitability to contribute to cardiac disease
Cardiac excitability and arrhythmia generation is critically dependent on the gating of multiple ion channel proteins

Summary

Introduction

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. 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. Palmitoylation is likely an important regulator of ion channel activity, evidence for the direct influence of palmitoylation on cellular excitability, and its potential involvement in cardiac sodium channelopathies, is lacking. A previously identified disease mutation in Nav1.5 associated with cardiac arrhythmia illustrates how the potential loss of palmitoylation at this crucial residue alters channel inactivation and dysregulates myocyte excitability to contribute to cardiac disease. Palmitoylation of Nav1.5 may represent a new target in treating cardiac diseases

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