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This Article Full Text Full Text (PDF) Buy All Versions of this Article: 297/4/H1446    most recent 00513.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Valdivia, C. R. Articles by Makielski, J. C. PubMed PubMed Citation Articles by Valdivia, C. R. Articles by Makielski, J. C.

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

¹Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin and ²Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics/Divisions of Cardiovascular Diseases and Pediatric Cardiology and the WindlandSmith Rice Comprehensive Sudden Cardiac Death Program, Mayo Clinic, Rochester, Minnesota

Submitted June 5, 2009 ; accepted in final form August 2, 2009

The SCN5A-encoded cardiac sodium channel underlies excitability in the heart, and dysfunction of sodium current (I_Na) 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 I_Na. 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 I_Na and excitability and may be important more generally in cardiac ischemia and heart failure.

cardiac arrhythmia; sodium current; ion channel; cell metabolism; glycerol 3-phosphate dehydrogenase 1-like; protein kinase C; cardiac sodium channel -subunit