Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation

Chiang, David Y.; Li, Na; Wang, Qiongling; Alsina, Katherina M.; Quick, Ann P.; Reynolds, Julia O.; Wang, Guoliang; Skapura, Darlene G.; Voigt, Niels; Dobrev, Dobromir; Wehrens, Xander H.T.

doi:10.1093/cvr/cvu123

Cited by 58 publications

(55 citation statements)

References 39 publications

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“…In line with these current observations, a few recent studies also have shown the similar findings. 2, 3, 6 Further studies are needed to delineate the mechanisms underlying the differential responses in atria and ventricle.…”

Section: Discussionmentioning

confidence: 99%

“…18 1000μg of lysates was suspended with lysis buffer: 1% CHAPS in 1000μl RIPA buffer (pH 7.4) containing 150 mM NaCl, 10 mM Tis-HCl, 20 mM NaF, 1 mM NaVO 3 and protease and phosphatase inhibitor cocktails (cOmplete, Mini and PhosSTOP from Roche Applied Science, Indianapolis, IN). The samples were incubated at 4 °C with 3μl of RyR2 antibody (MA3-916; Thermo Scientific) or mouse IgG (M5284; Sigma) and rotated overnight.…”

Section: Methodsmentioning

confidence: 99%

“…1 Emerging evidence suggests a central role for ryanodine receptor type-2 (RyR2) in AF development including both initiation and maintenance of AF. 2, 3 Specifically, inappropriate diastolic Ca 2+ -release from the sarcoplasmic reticulum (SR) through RyR2 has been causally linked to both atrial ectopic activity as well as atrial remodeling critical for AF maintenance and progression. 2, 4 In chronic AF (cAF), hyperactivity of RyR2 has been attributed to RyR2 hyperphosphorylation caused by overactive kinases.…”

Section: Introductionmentioning

confidence: 99%

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Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release

Chiang

Kongchan

Beavers

et al. 2014

Circ: Arrhythmia and Electrophysiology

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101

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Background Enhanced sarcoplasmic reticulum (SR) Ca2+-leak via ryanodine receptor type-2 (RyR2) contributes to the pathogenesis of atrial fibrillation (AF). Recent studies have shown that the level of RyR2 protein is elevated in atria of paroxysmal AF (pAF) patients, suggesting that microRNA-mediated post-transcriptional regulation of RyR2 might be an underlying mechanism. Bioinformatic analysis suggests that miR-106b and miR-93, members of the miR-106b-25 cluster, could bind to RYR2-3′UTR and suppress its translation. Thus, we tested the hypothesis that loss of the miR-106b-25 cluster promotes AF via enhanced RyR2-mediated SR Ca2+-leak. Methods and Results Quantitative real-time PCR showed that the levels of mature miR-106b, miR-93 and miR-25 were lower in atria of pAF patients compared with patients with sinus rhythm. In vitro assay showed that miR-93 reduced RYR2-3′UTR luciferase activity. Total RyR2 protein in atrial tissue of miR-106b-25−/− mice was increased by 42% compared to wild-type (WT) littermates, but still maintained a normal subcellular distribution. Ca2+-spark frequency and total SR Ca2+-leak were increased in atrial myocytes of miR-106b-25−/− mice. Telemetry ECG recordings revealed that miR-106b-25−/− mice exhibited more frequent atrial ectopy and were also more susceptible to pacing-induced AF than WT littermates. Increased SR Ca2+-release and AF susceptibility in miR-106b-25−/− mice were abolished by the RyR2-blocker K201. Conclusions These results suggest that miR-106b-25 cluster mediated post-transcriptional regulation of RyR2 is a potential molecular mechanism involved in pAF pathogenesis. As such, the miR-106b-25 cluster could be a novel gene-therapy target in AF associated with enhanced RyR2 expression.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release

Chiang

Kongchan

Beavers

et al. 2014

Circ: Arrhythmia and Electrophysiology

Self Cite

101

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“…[15] Since PP1 is believed to be primarily targeted to RyR2 via the R-subunit spinophilin ( Ppp1r9b ),[16] we studied the spinophilin knockout mouse and found a reduction in the association of PP1 with RyR2 by 70% while the global PP1 level was unchanged. [17] At the whole animal level, this disruption of PP1’s regulation of RyR2 also resulted in increased atrial ectopy and susceptibility to pacing-induced AF. [17] This study demonstrated for the first time that targeted disruption of PP1’s local regulation could have profound phenotypical consequences.…”

Section: Fundamental Challenge In Studying Pp1mentioning

confidence: 99%

Regulating the regulator: Insights into the cardiac protein phosphatase 1 interactome

Chiang

Heck

Dobrev

et al. 2016

Journal of Molecular and Cellular Cardiology

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Reversible phosphorylation of proteins is a delicate yet dynamic balancing act between kinases and phosphatases, the disturbance of which underlies numerous disease processes. While our understanding of protein kinases has grown tremendously over the past decades, relatively little is known regarding protein phosphatases. This may be because protein kinases are great in number and relatively specific in function, and thereby amenable to be studied in isolation, whereas protein phosphatases are much less abundant and more unspecific in their function. To achieve subcellular localization and substrate specificity, phosphatases depend on partnering with a large number of regulatory subunits, protein scaffolds and/or other interactors. This added layer of complexity presents a significant barrier to their study, but holds the key to unexplored opportunities for novel pharmacologic intervention. In this review we focus on the serine/threonine protein phosphatase type-1 (PP1), which plays an important role in cardiac physiology and pathophysiology. Although much work has been done to investigate the role of PP1 in cardiac diseases including atrial fibrillation and heart failure, most of these studies were limited to examining and manipulating the catalytic subunit(s) of PP1 without adequately considering the PP1 interactors, which give specificity to PP1’s functions. To complement these studies, three unbiased methods have been developed and applied to the mapping of the PP1 interactome: bioinformatics approaches, yeast two-hybrid screens, and affinity-purification mass spectrometry. The application of these complementary methods has the potential to generate a detailed cardiac PP1 interactome, which is an important step in identifying novel and targeted pharmacological interventions.

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“…Since protein phosphatases regulate RyR2 locally by counteracting CaMKII phosphorylation of RyR2 [29] and are a conserved serine/threonine phosphatase [30], we investigated the phosphorylation of PP1 and PP2A in cardiomyocytes under either high glucose or high [Zn 2+ ] i . As can be seen from Fig.…”

Section: Effect Of Increased [Zn 2+ ] I Level On Phosphorylation Levementioning

confidence: 99%

Intracellular Zn2+ Increase in Cardiomyocytes Induces both Electrical and Mechanical Dysfunction in Heart via Endogenous Generation of Reactive Nitrogen Species

Tuncay

Turan

2015

Biol Trace Elem Res

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Oxidants increase intracellular free Zn(2+) concentration ([Zn(2+)]i) in ventricular myocytes, which contributes to oxidant-induced alterations in excitation-contraction coupling (ECC). However, it is not clear whether increased [Zn(2+)]i in cardiomyocytes via increased reactive nitrogen species (RNS) has a role on heart function under pathological conditions, such as hyperglycemia. In this study, first we aimed to investigate the role of increased [Zn(2+)]i under in vitro condition in the development of both electrical and mechanical dysfunction of isolated papillary muscle strips from rat heart via exposed samples to a Zn(2+)-ionophore (Zn-pyrithione; 1 μM) for 20 min. Under simultaneous measurement of intracellular action potential and contractile activity in these preparations, Zn-pyrithione exposure caused marked prolongation in action potential repolarization phase and slowdown in both contraction and relaxation rates of twitch activity. Second, in order to demonstrate an association between increased [Zn(2+)]i and increased RNS, we monitored intracellular [Zn(2+)]i under an acute exposure of nitric oxide (NO) donor sodium nitroprusside, SNP, in freshly isolated quiescent cardiomyocytes loaded with FluoZin-3. Resting level of free Zn(2+) is significantly higher in cardiomyocytes under hyperglycemic condition compared to those of the controls, which seems to be associated with increased level of RNS production in hyperglycemic cardiomyocytes. Western blot analysis showed that Zn-pyrithione exposure induced a marked decrease in the activity of protein phosphatase 1 and 2A, member of macromolecular protein complex of cardiac ryanodine receptors, RyR2, besides significant increase in the phosphorylation level of extracellular signal-regulated kinase1/2 as a concentration-dependent manner. Overall, the present data demonstrated that there is a cross-relationship between increased RNS production and increased [Zn(2+)]i level in cardiomyocytes under pathological conditions such as hyperglycemia.

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Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation

Cited by 58 publications

References 39 publications

Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release

Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release

Regulating the regulator: Insights into the cardiac protein phosphatase 1 interactome

Intracellular Zn2+ Increase in Cardiomyocytes Induces both Electrical and Mechanical Dysfunction in Heart via Endogenous Generation of Reactive Nitrogen Species

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