Regulation of the cardiac sodium pump

Fuller, William; Tulloch, L.B.; Shattock, Michael J.; Calaghan, Sarah; Howie, J. W.; Wypijewski, Krzysztof

doi:10.1007/s00018-012-1134-y

Cited by 63 publications

(62 citation statements)

References 230 publications

(386 reference statements)

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“…However, although four α and three β subunit isoforms have been found, only α 1 , α 2 and β 1 are expressed at significant levels in cardiac myocytes [42,18]. In cardiac myocytes, a differential expression of Na/K isoforms in the sarcolemmal membrane, with α 2 subunits found more predominantly at the t-tubules, has been reported [1,65].…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…In both formulations, the two ionic factors remain inhibited in the absence of their respective species, gradually increasing for increasing intracellular Na + and extracellular K + concentrations (Figure 2A). Small changes in intracellular Na + elicit larger changes in pump activity [18], reflected by a larger γ Na compared to γ K in most model parameterizations of the pump. Finally, the f v term represents the voltage rectification of the Na/K pump, which usually also accounts for the additional modulation of Na/K activity by extracellular Na + concentration ( Figure 2B) [39], as experimentally reported [46].…”

Section: Mathematical Models Of the Cardiac Na/k Pump Currentmentioning

confidence: 99%

“…Under the effects of most cardiac glycosides, Na/K current block shortens action potential duration (APD), an action a priori unexpected since the blockade of an outward current should presumably prolong APD (as yet assumed in a number of recent studies on the pump [5,18]). However, this modulation of action potential repolarization occurs through a biphasic mechanism ( Figure 4A), in which APD is initially notably prolonged after Na/K current reduction, then followed by a progressive shortening below its control value, which is well documented [26,30,31,33,37,38,75].…”

Section: Multi-scale Studies Of Na/k Pump Regulation Of Cardiac Repolmentioning

confidence: 99%

“…To render an even more complicated picture, further signaling pathways such as nitric oxide stimulation of the Na/K pump [73], the role of oxidant stress on reducing the pump current [61], Na/K inhibition by PLM palmitoylation [68], or Na/K regulation by acetylcholine, insulin or hormones [23], are nowadays also well established. As noted by Fuller et al, "the consequences of the simultaneous activation of all the signaling pathways [...] are hard to predict, and the balance between them will undoubtedly vary between health and disease" [18]. The use of electrophysiological models incorporating metabolic regulation and up-to-date knowledge on the complete adrenergic stimulation cascade might therefore provide newer insights into how the concurrent activation of these regulatory agents influences Na/K pump activity and cellular electrophysiology, in particular under conditions of impaired metabolic supply, such as myocardial ischemia.…”

Section: +mentioning

confidence: 99%

“…The sodium-potassium pump (Na/K pump), also known as Na + ,K + -ATPase, is the principal mechanism for active ion transport across the membrane of excitable cells [2,18,20,64]. First discovered by the Danish scientist Jens Christian Skou in 1957 in his studies in the crab nerve [62], its ubiquitous importance for basic cell physiology and clinical practice was later recognized by the award of the Nobel Prize in Chemistry in 1997.…”

Section: Introductionmentioning

confidence: 99%

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Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Bueno‐Orovio

Sánchez

Pueyo

et al. 2013

Pflugers Arch - Eur J Physiol

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The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the Systems Biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate-dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

Section: Mathematical Models Of the Cardiac Na/k Pump Currentmentioning

confidence: 99%

Section: Multi-scale Studies Of Na/k Pump Regulation Of Cardiac Repolmentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Bueno‐Orovio

Sánchez

Pueyo

et al. 2013

Pflugers Arch - Eur J Physiol

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Na⁺, K⁺‐ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells

et al. 2018

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Na+, K+‐ATPase (NKA) activity, which establishes the sodium and potassium gradient across the cell membrane and is instrumental in the propagation of the nerve impulses, is altered in a number of neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD). In the present work, we examined a wide range of biochemical and cellular parameters in the attempt to understand the reason(s) for the severe decrease in NKA activity in erythrocytes of ASD children that we reported previously. NKA activity in leukocytes was found to be decreased independently from alteration in plasma membrane fluidity. The different subunits were evaluated for gene expression in leukocytes and for protein expression in erythrocytes: small differences in gene expression between ASD and typically developing children were not apparently paralleled by differences in protein expression. Moreover, no gross difference in erythrocyte plasma membrane oxidative modifications was detectable, although oxidative stress in blood samples from ASD children was confirmed by increased expression of NRF2 mRNA. Interestingly, gene expression of some NKA subunits correlated with clinical features. Excess inhibitory metals or ouabain‐like activities, which might account for NKA activity decrease, were ruled out. Plasma membrane cholesterol, but not phosphatidylcholine and phosphatidlserine, was slighty decreased in erythrocytes from ASD children. Although no compelling results were obtained, our data suggest that alteration in the erytrocyte lipid moiety or subtle oxidative modifications in NKA structure are likely candidates for the observed decrease in NKA activity. These findings are discussed in the light of the relevance of NKA in ASD. Autism Res 2018, 11: 1388–1403. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.Lay SummaryThe activity of the cell membrane enzyme NKA, which is instrumental in the propagation of the nerve impulses, is severely decreased in erythrocytes from ASD children and in other brain disorders, yet no explanation has been provided for this observation. We strived to find a biological/biochemical cause of such alteration, but most queries went unsolved because of the complexity of NKA regulation. As NKA activity is altered in many brain disorders, we stress the relevance of studies aimed at understanding its regulation in ASD.

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The role of post‐translational modifications in acute and chronic cardiovascular disease

Smith

White

2014

Proteomics Clinical Apps

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Cardiovascular disease (CVD) in one of the leading causes of mortality and morbidity worldwide, accounting for both primary diseases of the heart and vasculature and arising as a co-morbidity with numerous pathologies, including type 2 diabetes mellitus (T2DM). There has been significant emphasis on the role of the genome in CVD, aiding in the definition of 'at-risk' patients. The extent of disease penetrance however, can be influenced by environmental factors that are not detectable by investigating the genome alone. By targeting the transcriptome in response to CVD, the interplay between genome and environment is more apparent, however this implies the level of protein expression without reference to proteolytic turnover, or potentially more importantly, without defining the role of PTMs in the development of disease. Here, we discuss the role of both brief and irreversible PTMs in the setting of myocardial ischemia/reperfusion injury. Key proteins involved in calcium regulation have been observed as differentially modified by phosphorylation/O-GlcNAcylation or phosphorylation/redox modifications, with the level of interplay dependent on the physiological or pathophysiological state. The ability to modify crucial sites to produce the desired functional output is modulated by the presence of other PTMs as exemplified in the T2DM heart, where hyperglycemia results in aberrant O-GlcNAcylation and advanced glycation end products. By using the signalling events predicted to be critical to post-conditioning, an intervention with great promise for the cardioprotection of the ischemia/reperfusion injured heart, as an example, we discuss the level of PTMs and their interplay. The inability of post-conditioning to protect the diabetic heart may be regulated by aberrant PTMs influencing those sites necessary for protection.

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Regulation of the cardiac sodium pump

Cited by 63 publications

References 230 publications

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Na⁺, K⁺‐ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells

The role of post‐translational modifications in acute and chronic cardiovascular disease

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Regulation of the cardiac sodium pump

Cited by 63 publications

References 230 publications

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Na+, K+‐ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells

The role of post‐translational modifications in acute and chronic cardiovascular disease

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Product

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Na⁺, K⁺‐ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells