Cardiac Na
            <sup>+</sup>
            Current Regulation by Pyridine Nucleotides

Liu, Man; Sanyal, Shamarendra; Gao, Ge; Gurung, Iman S.; Zhu, Xiaodong; Gaconnet, Georgia; Kerchner, Laurie J.; Shang, Lijuan L.; Huang, Christopher; Grace, Andrew A.; London, Barry; Dudley, Samuel C.

doi:10.1161/circresaha.109.197277

Cited by 106 publications

(148 citation statements)

References 55 publications

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“…The observation of NADH-induced ROS production in our study is consistent with others (27)(28)(29)(37)(38)(39). However, the mechanism is not well understood.…”

Section: Discussionsupporting

confidence: 87%

“…Alterations in NADH/NAD ϩ ratio not only reflect abnormal redox and metabolic conditions but can also play a primary role in the regulation of ion channels. Recent studies demonstrated that NADH inhibits the Na ϩ current (27,28) and increases spontaneous SR Ca 2ϩ release (29) in cardiomyocytes. A sustained elevation of cytosolic NADH can occur under ischemic or hypoxic conditions, which was mimicked in this work by raising cytoplasmic NADH via the patch pipette or by increasing the NADH/NAD ϩ redox potential with lactate treatment, leading to a marked inhibition of I NCX.…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanism is not well understood. A mechanism of NADHinduced ROS accumulation was proposed in a recent study (27,28) in HEK cells and neonatal rat ventricular myocytes, demonstrating that NADH inhibited cardiac Na ϩ current (I Na ) by evoking mitochondrial overproduction of ROS. This effect was dependent on PKC activation and mitochondrial function and was blocked by inhibitors of complexes I and II, rotenone and malonate, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Liu

O’Rourke

2013

Journal of Biological Chemistry

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Background: Regulation of the sarcolemmal Na ϩ /Ca 2ϩ exchanger (NCX) modulates cardiac excitation-contraction coupling, and NCX contributes to ischemia-reperfusion injury. Results: Increased cytosolic NADH inhibits NCX through a ROS-dependent mechanism. Conclusion: Regulation by cytosolic NADH reveals a novel way that NCX responds to changes in energy metabolism. Significance: NADH-dependent regulation of NCX regulation represents a potential therapeutic target for ameliorating ischemia-reperfusion injury or chronic cardiovascular disease.

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“…The observation of NADH-induced ROS production in our study is consistent with others (27)(28)(29)(37)(38)(39). However, the mechanism is not well understood.…”

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Liu

O’Rourke

2013

Journal of Biological Chemistry

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“…The latter gene defect has been suggested to cause suppression of the Na + current by a PKC-dependent mechanism that is linked with the redox state of the cell (103,104). Specifically, reduced enzymatic activity of mutant GPD1L is associated with an NADH/NAD + imbalance that can activate protein kinase C and lead to phosphorylation of a specific serine residue (Ser1503) on Na V 1.5, causing reduced channel activity.…”

Section: Figurementioning

confidence: 99%

Molecular and genetic basis of sudden cardiac death

George

2013

J. Clin. Invest.

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The abrupt cessation of effective cardiac function due to an aberrant heart rhythm can cause sudden and unexpected death at any age, a syndrome called sudden cardiac death (SCD). Annually, more than 300,000 cases of SCD occur in the United States alone, making this a major public health concern. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of heart rhythm. This knowledge has helped shape the current diagnosis and treatment of inherited arrhythmia susceptibility syndromes associated with SCD and has provided a pathophysiological framework for understanding more complex conditions predisposing to this tragic event. This Review presents an overview of the molecular basis of SCD, with a focus on monogenic arrhythmia syndromes.

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“…Interestingly, mutations in the gene encoding glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), which cause Brugada syndrome and sudden infant death syndrome, have been shown to reduce SCN5A current (24,34). Recent studies (24,33) have implicated the downregulation of cell surface Na ϩ channels by PKC activation as the likely mechanism for this effect, although other data have suggested that the mechanism may be more complex (23). These data regarding GPD1L mutations further support a clinically important role for PKC-mediated regulation of cardiac I Na in the generation of serious cardiac arrhythmias.…”

mentioning

confidence: 99%

Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na⁺channels

Hallaq¹,

Wang²,

Kunic³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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ϩ current derived from expression of the cardiac isoform SCN5A is reduced by receptor-mediated or direct activation of protein kinase C (PKC). Previous work has suggested a possible role for loss of Na ϩ channels at the plasma membrane in this effect, but the results are controversial.In this study, we tested the hypothesis that PKC activation acutely modulates the intracellular distribution of SCN5A channels and that this effect can be visualized in living cells. In human embryonic kidney cells that stably expressed SCN5A with green fluorescent protein (GFP) fused to the channel COOH-terminus (SCN5A-GFP), Na ϩ currents were suppressed by an exposure to PKC activation. Using confocal microscopy, colocalization of SCN5A-GFP channels with the plasma membrane under control and stimulated conditions was quantified. A separate population of SCN5A channels containing an extracellular epitope was immunolabeled to permit temporally stable labeling of the plasma membrane. Our results demonstrated that Na ϩ channels were preferentially trafficked away from the plasma membrane by PKC activation, with a major contribution by Ca 2ϩ -sensitive or conventional PKC isoforms, whereas stimulation of protein kinase A (PKA) had the opposite effect. Removal of the conserved PKC site Ser 1503 or exposure to the NADPH oxidase inhibitor apocynin eliminated the PKC-mediated effect to alter channel trafficking, indicating that both channel phosphorylation and ROS were required. Experiments using fluorescence recovery after photobleaching demonstrated that both PKC and PKA also modified channel mobility in a manner consistent with the dynamics of channel distribution. These results demonstrate that the activation of protein kinases can acutely regulate the intracellular distribution and molecular mobility of cardiac Na ϩ channels in living cells.

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Cardiac Na ⁺ Current Regulation by Pyridine Nucleotides

Cited by 106 publications

References 55 publications

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Molecular and genetic basis of sudden cardiac death

Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na⁺channels

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Cardiac Na + Current Regulation by Pyridine Nucleotides

Cited by 106 publications

References 55 publications

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Molecular and genetic basis of sudden cardiac death

Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na+channels

Contact Info

Product

Resources

About

Cardiac Na ⁺ Current Regulation by Pyridine Nucleotides

Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na⁺channels