Serine/Threonine Phosphatases in Atrial Fibrillation

Heijman, Jordi; Ghezelbash, Shokoufeh; Wehrens, Xander H.T.; Dobrev, Dobromir

doi:10.1016/j.yjmcc.2016.12.009

Cited by 33 publications

(26 citation statements)

References 131 publications

(192 reference statements)

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“…14 Nevertheless, the majority of studies exploring dysregulation of RyR2 in AF have shown that hyperphosphorylation of RyR2 at residues S2814 and S2808 promotes SR-Ca 2+ leak, spontaneous Ca 2+ -release events, and delayed afterdepolarizations that may underlie arrhythmogenic triggered activity in atrial cardiomyocytes. 21,35,36 Phosphorylation of RyR2 is mediated by PKA and CaMKII, whereas Table II in the online-only Data Supplement), profiling shows comigration of PLN/ SERCA2a and RyR2 in higher-molecular-weight complexes (>1 MDa) and, in addition, JPH2 (≤1 MDa). In contrast, in pAF the RyR2 channel was nearly abolished in higher-molecular-weight complexes, and only monomeric JPH2 exists.…”

Section: Ryr2 Regulation By Pp1 In Afmentioning

confidence: 99%

“…However, it is still incompletely understood which RyR2 phosphorylation sites are dephosphorylated by PP1 and protein phosphatase 2A. 21 Chiang et al 22 demonstrated that PP1 R-subunit PPP1R9B (spinophilin) targets PP1c to RyR2. However, genetic ablation of spinophilin in mice reduced PP1c binding to RyR2 by only ≈60%, suggesting that PP1c may bind to the channel through alternative targeting mechanism(s).…”

Section: Ryr2 Regulation By Pp1 In Afmentioning

confidence: 99%

“…13,19,20 Protein phosphatase type 1 (PP1)-one of the most abundant serine-threonine phosphatases in the heartdephosphorylates both RyR2 and PLN. 21 Proper targeting of the PP1-catalytic (PP1c) subunit depends on a variety of regulatory subunits (R-subunits) that confer substrate specificity, and we have recently shown that altered binding between PP1c and its R-subunits may contribute to impaired phosphatase targeting in AF. 19,22 For example, PP1c is targeted to RyR2 by the R-subunit PPP1R9B (spinophilin).…”

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Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation

et al. 2019

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Background: Abnormal calcium (Ca 2+ ) release from the sarcoplasmic reticulum (SR) contributes to the pathogenesis of atrial fibrillation (AF). Increased phosphorylation of 2 proteins essential for normal SR-Ca 2+ cycling, the type-2 ryanodine receptor (RyR2) and phospholamban (PLN), enhances the susceptibility to AF, but the underlying mechanisms remain unclear. Protein phosphatase 1 (PP1) limits steady-state phosphorylation of both RyR2 and PLN. Proteomic analysis uncovered a novel PP1-regulatory subunit (PPP1R3A [PP1 regulatory subunit type 3A]) in the RyR2 macromolecular channel complex that has been previously shown to mediate PP1 targeting to PLN. We tested the hypothesis that reduced PPP1R3A levels contribute to AF pathogenesis by reducing PP1 binding to both RyR2 and PLN. Methods: Immunoprecipitation, mass spectrometry, and complexome profiling were performed from the atrial tissue of patients with AF and from cardiac lysates of wild-type and Pln -knockout mice. Ppp1r3a -knockout mice were generated by CRISPR-mediated deletion of exons 2 to 3. Ppp1r3a -knockout mice and wild-type littermates were subjected to in vivo programmed electrical stimulation to determine AF susceptibility. Isolated atrial cardiomyocytes were used for Stimulated Emission Depletion superresolution microscopy and confocal Ca 2+ imaging. Results: Proteomics identified the PP1-regulatory subunit PPP1R3A as a novel RyR2-binding partner, and coimmunoprecipitation confirmed PPP1R3A binding to RyR2 and PLN. Complexome profiling and Stimulated Emission Depletion imaging revealed that PLN is present in the PPP1R3A-RyR2 interaction, suggesting the existence of a previously unknown SR nanodomain composed of both RyR2 and PLN/sarco/endoplasmic reticulum calcium ATPase-2a macromolecular complexes. This novel RyR2/PLN/sarco/endoplasmic reticulum calcium ATPase-2a complex was also identified in human atria. Genetic ablation of Ppp1r3a in mice impaired binding of PP1 to both RyR2 and PLN. Reduced PP1 targeting was associated with increased phosphorylation of RyR2 and PLN, aberrant SR-Ca 2+ release in atrial cardiomyocytes, and enhanced susceptibility to pacing-induced AF. Finally, PPP1R3A was progressively downregulated in the atria of patients with paroxysmal and persistent (chronic) AF. Conclusions: PPP1R3A is a novel PP1-regulatory subunit within the RyR2 channel complex. Reduced PPP1R3A levels impair PP1 targeting and increase phosphorylation of both RyR2 and PLN. PPP1R3A deficiency promotes abnormal SR-Ca 2+ release and increases AF susceptibility in mice. Given that PPP1R3A is downregulated in patients with AF, this regulatory subunit may represent a new target for AF therapeutic strategies.

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Section: Ryr2 Regulation By Pp1 In Afmentioning

confidence: 99%

Section: Ryr2 Regulation By Pp1 In Afmentioning

confidence: 99%

mentioning

confidence: 99%

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Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation

et al. 2019

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“…The activity, specificity and subcellular localization of the PP2A heterotrimeric holoenzyme complex, are highly regulated through the interaction of regulatory B subunit family members with the substrates [ 6 ]. PP2A contributes to a central role in cardiac diseases [ 7 – 9 ]. Transgenic mouse lines expressing either mutated structural A subunits or catalytic C subunits exhibit a cardiac phenotype resembling dilated cardiomyopathy [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Deletion of Pr72 causes cardiac developmental defects in Zebrafish

Song

Han

et al. 2018

PLoS ONE

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The alpha regulator subunit B'' of protein phosphatase 2 (PPP2R3A), a regulatory subunit of protein phosphatase 2A (PP2A), was reported to present a special subcellular localization in cardiomyocytes and elevate in non-ischemia failing hearts. PPP2R3A has two transcriptions PR72 and PR130. PR72 acts as a negative regulator of the Wnt signaling cascade, while the Wnt signaling cascade plays a pivotal role in cardiac development. And PR130 was found to be involved in cardiac development of zebrafish in our previous study. Thus, to investigate the function of PR72 in heart, two stable pr72 knockout (KO) zebrafish lines were generated using Transcription Activator-Like Effector Nuclease (TALEN) technology. Homozygous pr72 KO fish struggled to survive to adulthood and exhibited cardiac developmental defects, including enlarged ventricular chambers, reduced cardiomyocytes and decreased cardiac function. And the defective sarcomere ultrastructure that affected mitochondria, I bands, Z lines, and intercalated disks was also observed. Furthermore, the abnormal heart looping was detected in mutants which could be rescued by injection with wild type pr72 mRNA. Additionally, it was found that Wnt effectors were elevated in mutants. Those indicated that deletion of pr72 in zebrafish interrupted cardiac development, probably through activation of the Wnt pathway.

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“…Due to the single-source, minimalistic philosophy of the approach, there are many factors which play a role in human atrial electrophysiology which have not been included, due to a lack of well characterized and human atrial specific data. For example, the models do not contain detailed descriptions of phosphorylation due to PKA, or the impact of CaMKII (and serine and threonine; Heijman et al, 2014 , 2017 ; Mesubi and Anderson, 2016 ), or additional currents such as small conductance potassium channels ( Skibsbye et al, 2014 ), which may have an important influence on human atrial cell dynamics in control and perturbed conditions. Exclusion of these components is not a claim that they are unimportant, but rather follows from the motivation not to introduce sophistication and complexity by including components which have not been well characterized in the human atria (and specifically the WL) and thus contain potential sources of error, ad hoc parameters, or inaccurately scaled contributions.…”

Section: Discussionmentioning

confidence: 99%

Description of the Human Atrial Action Potential Derived From a Single, Congruent Data Source: Novel Computational Models for Integrated Experimental-Numerical Study of Atrial Arrhythmia Mechanisms

et al. 2018

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Introduction: The development of improved diagnosis, management, and treatment strategies for human atrial fibrillation (AF) is a significant and important challenge in order to improve quality of life for millions and reduce the substantial social-economic costs of the condition. As a complex condition demonstrating high variability and relation to other cardiac conditions, the study of AF requires approaches from multiple disciplines including single-cell experimental electrophysiology and computational modeling. Models of human atrial cells are less well parameterized than those of the human ventricle or other mammal species, largely due to the inherent challenges in patch clamping human atrial cells. Such challenges include, frequently, unphysiologically depolarized resting potentials and thus injection of a compensatory hyperpolarizing current, as well as detecting certain ion currents which may be disrupted by the cell isolation process. The aim of this study was to develop a laboratory specific model of human atrial electrophysiology which reproduces exactly the conditions of isolated-cell experiments, including testing of multiple experimental interventions.Methods: Formulations for the primary ion currents characterized by isolated-cell experiments in the Workman laboratory were fit directly to voltage-clamp data; the fast sodium-current was parameterized based on experiments relating resting membrane potential to maximal action potential upstroke velocity; compensatory hyperpolarizing current was included as a constant applied current. These formulations were integrated with three independent human atrial cell models to provide a family of novel models. Extrapolated intact-cell models were developed through removal of the hyperpolarizing current and introduction of terminal repolarization potassium currents.Results: The isolated-cell models quantitatively reproduced experimentally measured properties of excitation in both control and pharmacological and dynamic-clamp interventions. Comparison of isolated and intact-cell models highlighted the importance of reproducing this cellular environment when comparing experimental and simulation data.Conclusion: We have developed a laboratory specific model of the human atrial cell which directly reproduces the experimental isolated-cell conditions and captures human atrial excitation properties. The model may be particularly useful for directly relating model to experiment, and offers a complementary tool to the available set of human atrial cell models with specific advantages resulting from the congruent input data source.

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Serine/Threonine Phosphatases in Atrial Fibrillation

Cited by 33 publications

References 131 publications

Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation

Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation

Deletion of Pr72 causes cardiac developmental defects in Zebrafish

Description of the Human Atrial Action Potential Derived From a Single, Congruent Data Source: Novel Computational Models for Integrated Experimental-Numerical Study of Atrial Arrhythmia Mechanisms

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