GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A

Carmen R. Valdivia, Kazuo Ueda, Michael John Ackerman, Jonathan C. Makielski

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

The SCN5A-encoded cardiac sodium channel underlies excitability in the heart, and dysfunction of sodium current (INa) can cause fatal ventricular arrhythmia in maladies such as long QT syndrome, Brugada syndrome (BrS), and sudden infant death syndrome (SIDS). The gene GPD1L encodes the glycerol phosphate dehydrogenase 1-like protein with homology to glycerol phosphate dehydrogenase (GPD1), but the function for this enzyme is unknown. Mutations in GPD1L have been associated with BrS and SIDS and decrease I Na through an unknown mechanism. Using a heterologous expression system, we show that GPD1L associated with SCN5A and that the BrS- and SIDS-related mutations in GPD1L caused a loss of enzymatic function resulting in glycerol-3-phosphate PKC-dependent phosphorylation of SCN5A at serine 1503 (S1503) through a GPD1L-dependent pathway. The direct phosphorylation of S1503 markedly decreased INa. These results show a function for GPD1L in cell physiology and a mechanism linking mutations in GPD1L to sudden cardiac arrest. Because the enzymatic step catalyzed by GPD1L depends upon nicotinamide adenine dinucleotide, this GPD1L pathway links the metabolic state of the cell to INa and excitability and may be important more generally in cardiac ischemia and heart failure.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number4
DOIs
StatePublished - Oct 2009

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Brugada Syndrome
Sudden Infant Death
Sodium Channels
Oxidation-Reduction
Phosphorylation
glycerol dehydrogenase
Serine
Mutation
Heart Failure
Long QT Syndrome
Cell Physiological Phenomena
Sudden Cardiac Death
Metabolic Networks and Pathways
NAD
Cardiac Arrhythmias
Ischemia
Sodium
Phosphates
Enzymes
Genes

Keywords

  • Cardiac arrhythmia
  • Cardiac sodium channel α-subunit
  • Cell metabolism
  • Glycerol 3-phosphate dehydrogenase 1-like
  • Ion channel
  • Protein kinase C
  • Sodium current

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A. / Valdivia, Carmen R.; Ueda, Kazuo; Ackerman, Michael John; Makielski, Jonathan C.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 4, 10.2009.

Research output: Contribution to journalArticle

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