RATIONALE: Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na+ current (I(Na)) and cause Brugada Syndrome (BrS). GPD1-L has >80% amino acid homology with glycerol-3-phosphate dehydrogenase, which is involved in NAD-dependent energy metabolism. OBJECTIVE: Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na(v)1.5). METHODS AND RESULTS: HEK293 cells stably expressing Na(v)1.5 and rat neonatal cardiomyocytes were used. The influence of NADH/NAD+ on arrhythmic risk was evaluated in wild-type or SCN5A(+/-) mouse heart. A280V GPD1-L caused a 2.48+/-0.17-fold increase in intracellular NADH level (P<0.001). NADH application or cotransfection with A280V GPD1-L resulted in decreased I(Na) (0.48+/-0.09 or 0.19+/-0.04 of control group, respectively; P<0.01), which was reversed by NAD+, chelerythrine, or superoxide dismutase. NAD+ antagonism of the Na+ channel downregulation by A280V GPD1-L or NADH was prevented by a protein kinase (PK)A inhibitor, PKAI(6-22). The effects of NADH and NAD+ were mimicked by a phorbol ester and forskolin, respectively. Increasing intracellular NADH was associated with an increased risk of ventricular tachycardia in wild-type mouse hearts. Extracellular application of NAD+ to SCN5A(+/-) mouse hearts ameliorated the risk of ventricular tachycardia. CONCLUSIONS: Our results show that Na(v)1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and I(Na). This effect required protein kinase C activation and was mediated by oxidative stress. NAD+ could prevent this effect by activating PKA. Mutations of GPD1-L may downregulate Na(v)1.5 by altering the oxidized to reduced NAD(H) balance.
RATIONALE: Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na+ current (I(Na)) and cause Brugada Syndrome (BrS). GPD1-L has >80% amino acid homology with glycerol-3-phosphate dehydrogenase, which is involved in NAD-dependent energy metabolism. OBJECTIVE: Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na(v)1.5). METHODS AND RESULTS:HEK293 cells stably expressing Na(v)1.5 and rat neonatal cardiomyocytes were used. The influence of NADH/NAD+ on arrhythmic risk was evaluated in wild-type or SCN5A(+/-) mouse heart. A280VGPD1-L caused a 2.48+/-0.17-fold increase in intracellular NADH level (P<0.001). NADH application or cotransfection with A280VGPD1-L resulted in decreased I(Na) (0.48+/-0.09 or 0.19+/-0.04 of control group, respectively; P<0.01), which was reversed by NAD+, chelerythrine, or superoxide dismutase. NAD+ antagonism of the Na+ channel downregulation by A280VGPD1-L or NADH was prevented by a protein kinase (PK)A inhibitor, PKAI(6-22). The effects of NADH and NAD+ were mimicked by a phorbol ester and forskolin, respectively. Increasing intracellular NADH was associated with an increased risk of ventricular tachycardia in wild-type mouse hearts. Extracellular application of NAD+ to SCN5A(+/-) mouse hearts ameliorated the risk of ventricular tachycardia. CONCLUSIONS: Our results show that Na(v)1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and I(Na). This effect required protein kinase C activation and was mediated by oxidative stress. NAD+ could prevent this effect by activating PKA. Mutations of GPD1-L may downregulate Na(v)1.5 by altering the oxidized to reduced NAD(H) balance.
Authors: G Alex Papadatos; Polly M R Wallerstein; Catherine E G Head; Rosemary Ratcliff; Peter A Brady; Klaus Benndorf; Richard C Saumarez; Ann E O Trezise; Christopher L-H Huang; Jamie I Vandenberg; William H Colledge; Andrew A Grace Journal: Proc Natl Acad Sci U S A Date: 2002-04-23 Impact factor: 11.205
Authors: Subrata Biswas; Deborah DiSilvestre; Yanli Tian; Victoria L Halperin; Gordon F Tomaselli Journal: Circ Res Date: 2009-03-05 Impact factor: 17.367
Authors: Ajit Vikram; Christopher M Lewarchik; Jin-Young Yoon; Asma Naqvi; Santosh Kumar; Gina M Morgan; Julia S Jacobs; Qiuxia Li; Young-Rae Kim; Modar Kassan; Jing Liu; Mohanad Gabani; Ajay Kumar; Haider Mehdi; Xiaodong Zhu; Xiaoqun Guan; William Kutschke; Xiaoming Zhang; Ryan L Boudreau; Shengchuan Dai; Daniel S Matasic; Saet-Byel Jung; Kenneth B Margulies; Vikas Kumar; Markus M Bachschmid; Barry London; Kaikobad Irani Journal: Nat Med Date: 2017-02-13 Impact factor: 53.440