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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Article number12035
JournalNature Communications
Volume7
DOIs
StatePublished - Jun 23 2016

Fingerprint

Lipoylation
arrhythmia
muscle cells
Sodium Channels
NAV1.5 Voltage-Gated Sodium Channel
Muscle Cells
availability
Cardiac Arrhythmias
Availability
deactivation
Cysteine
Post Translational Protein Processing
Sodium
cysteine
Action Potentials
mutations
Lipids
lipids
Brugada Syndrome
Substrates

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation. / Pei, Zifan; Xiao, Yucheng; Meng, Jingwei; Hudmon, Andy; Cummins, Theodore.

In: Nature Communications, Vol. 7, 12035, 23.06.2016.

Research output: Contribution to journalArticle

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AU - Cummins, Theodore

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