GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A.
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.
Valdivia
Carmen R
CR
Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Ueda
Kazuo
K
Ackerman
Michael J
MJ
Makielski
Jonathan C
JC
D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D005994:Glycerophosphates / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008564:Membrane Potentials; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012694:Serine; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013398:Sudden Infant Death / Q000235:genetics; D014162:Transfection; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
D005994:Glycerophosphates; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D047428:Protein Kinase Inhibitors; C470379:SCN1B protein, human; C568320:SCN5A protein, human; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D012694:Serine; D012964:Sodium; C525035:GPD1L protein, human; D005993:Glycerolphosphate Dehydrogenase; D011493:Protein Kinase C