Protein Carbonylation of an Amino Acid Residue of the Na/K‐ATPase α1 Subunit Determines Na/K‐ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells

Yan, Yanling; Shapiro, Anna P.; Chaudhry, Muhammad Anwar; Maxwell, Kyle; Drummond, Christopher A.; Kennedy, David J.; Tian, Jiang; Malhotra, Deepak; Xie, Zijian; Shapiro, Joseph I.; Liu, Jiang

doi:10.1161/jaha.116.003675

Cited by 36 publications

(57 citation statements)

References 64 publications

(212 reference statements)

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“…1 ). Our proposed Na/K-ATPase signaling mediated oxidant amplification loop is based on our previous model [59], as well as 4 major observations described below [31, 32, 56–58, 60]. First, exogenous CTS stimulates Na/K-ATPase/c-Src signaling (and as a consequence, ROS generation), but in addition, Na/K-ATPase/c- src signaling is also stimulated by increases in ROS alone (caused by a) exogenously added H 2 O 2 , or b) exogenous, extracellular glu- cose oxidase, which produces H 2 O 2 at the expense of glucose in the culture medium).…”

Section: The Interplay Of Na/k-atpase and Ros - A Positive-feedback Omentioning

confidence: 99%

Targeting Na/K-ATPase Signaling: A New Approach to Control Oxidative Stress

Liu

Lilly

Shapiro

2018

CPD

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Renal and cardiac function are greatly affected by chronic oxidative stress which can cause many pathophysiological states. The Na/K-ATPase is well-described as an ion pumping enzyme involved in maintaining cellular ion homeostasis; however, in the past two decades, extensive research has been done to understand the signaling function of the Na/K-ATPase and determine its role in physiological and pathophysiological states. Our lab has shown that the Na/K-ATPase signaling cascade can function as an amplifier of reactive oxygen species (ROS) which can be initiated by cardiotonic steroids or increases in ROS. Regulation of systemic oxidative stress by targeting Na/K-ATPase signaling mediated oxidant amplification improves 5/6th partial nephrectomy (PNx) mediated uremic cardiomyopathy, renal sodium handling, as well as ameliorates adipogenesis. This review will present this new concept of Na/K-ATPase signaling mediated oxidant amplification loop and its clinic implication.

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Section: The Interplay Of Na/k-atpase and Ros - A Positive-feedback Omentioning

confidence: 99%

Targeting Na/K-ATPase Signaling: A New Approach to Control Oxidative Stress

Liu

Lilly

Shapiro

2018

CPD

Self Cite

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“…As ROS can also initiate this sequence through altering Na/K-ATPase conformation and dis-inhibiting Src kinase, feed forward amplification results [18]. …”

Section: Extension Of the Markov Chain To Define The Oxidant Amplimentioning

confidence: 99%

“…However, it is fair to say that the model (as it was constructed to simulated this) does give roughly similar changes in Src phosphorylation and ROS generation (as well as cellular aging) as that seen in experimental systems [5,6,18,24,29,32]. In addition, there are several additional points which can be drawn:

The Na/K-ATPase can be viewed as existing in a superposition of states which relate to each other as a Markov chain.

The Na/K-ATPase interacts with Src and its other signaling partners using principles also seen with Markov chains.

…”

Section: Extension Of the Markov Chain To Define The Oxidant Amplimentioning

confidence: 99%

“…In addition, there are several additional points which can be drawn:

The Na/K-ATPase can be viewed as existing in a superposition of states which relate to each other as a Markov chain.

The Na/K-ATPase interacts with Src and its other signaling partners using principles also seen with Markov chains. This allows modeling to be developed using a system of ordinary differential equations.

As seen in biological systems, oxidant stress results from the shift in the Na/K-ATPase to the E2 state, which then becomes ineffective in inhibiting Src [18]. This leads to a cascade generating oxidants which further stimulates the Na/K-ATPase oxidant amplification loop (feed forward amplification) as well as oxidant injury consistent with aging.…”

Section: Extension Of the Markov Chain To Define The Oxidant Amplimentioning

confidence: 99%

“…

The Na/K-ATPase α1 subunit inhibits associated Src kinase while in the E1 state. This has been suggested by modeling studies that demonstrate a number of poses by which a peptide in the N domain of the α1 subunit of the Na/K-ATPase interacts with the kinase domain of Src while in the E1 state, but an absence of such poses for the E2 state [18].

Activation of Src kinase leads to transactivation of the epithelial growth factor receptor (EGFR) and downstream generation of reactive oxygen species.

…”

Section: Introductionmentioning

confidence: 99%

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Quantum Modeling: A Bridge between the Pumping and Signaling Functions of Na/K-ATPase

Wang

Shapiro

2018

IJMS

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Although the signaling function of Na/K-ATPase has been studied for decades, the chasm between the pumping function and the signaling function of Na/K-ATPase is still an open issue. This article explores the relationship between ion pumping and signaling with attention to the amplification of oxidants through this signaling function. We specifically consider the Na/K-ATPase with respect to its signaling function as a superposition of different states described for its pumping function. We then examine how alterations in the relative amounts of these states could alter signaling through the Src-EGFR-ROS pathway. Using assumptions based on some experimental observations published by our laboratories and others, we develop some predictions regarding cellular oxidant stress.

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Protein carbonylation causes sarcoplasmic reticulum Ca2+ overload by increasing intracellular Na+ level in ventricular myocytes

Bovo,

Seflova,

Robia

et al. 2024

Pflugers Arch - Eur J Physiol

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Diabetes is commonly associated with an elevated level of reactive carbonyl species due to alteration of glucose and fatty acid metabolism. These metabolic changes cause an abnormality in cardiac Ca 2+ regulation that can lead to cardiomyopathies. In this study, we explored how the reactive α-dicarbonyl methylglyoxal (MGO) affects Ca 2+ regulation in mouse ventricular myocytes. Analysis of intracellular Ca 2+ dynamics revealed that MGO (200 µM) increases action potential (AP)-induced Ca 2+ transients and sarcoplasmic reticulum (SR) Ca 2+ load, with a limited effect on L-type Ca 2+ channel-mediated Ca 2+ transients and SERCA-mediated Ca 2+ uptake. At the same time, MGO signi cantly slowed down cytosolic Ca 2+ extrusion by Na + /Ca 2+ exchanger (NCX). MGO also increased the frequency of Ca 2+ waves during rest and these Ca 2+ release events were abolished by an external solution with zero [Na + ] and [Ca 2+ ].Adrenergic receptor activation with isoproterenol (10 nM) increased Ca 2+ transients and SR Ca 2+ load, but it also triggered spontaneous Ca 2+ waves in 27% of studied cells. Pretreatment of myocytes with MGO increased the fraction of cells with Ca 2+ waves during adrenergic receptor stimulation by 163%.Measurements of intracellular [Na + ] revealed that MGO increases cytosolic [Na + ] by 57% from the maximal effect produced by the Na + -K + ATPase inhibitor ouabain (20 µM). This increase in cytosolic [Na + ] was a result of activation of a tetrodotoxin-sensitive Na + in ux, but not an inhibition of Na + -K +ATPase. An increase in cytosolic [Na + ] after treating cells with ouabain produced similar effects on Ca 2+ regulation as MGO. These results suggest that protein carbonylation can affect cardiac Ca 2+ regulation by increasing cytosolic [Na + ] via a tetrodotoxin-sensitive pathway. This, in turn, reduces Ca 2+ extrusion by NCX, causing SR Ca 2+ overload and spontaneous Ca 2+ waves.

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Protein Carbonylation of an Amino Acid Residue of the Na/K‐ATPase α1 Subunit Determines Na/K‐ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells

Cited by 36 publications

References 64 publications

Targeting Na/K-ATPase Signaling: A New Approach to Control Oxidative Stress

Targeting Na/K-ATPase Signaling: A New Approach to Control Oxidative Stress

Quantum Modeling: A Bridge between the Pumping and Signaling Functions of Na/K-ATPase

Protein carbonylation causes sarcoplasmic reticulum Ca2+ overload by increasing intracellular Na+ level in ventricular myocytes

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