ArticleCardiovascular research2014
Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation.
Article in Cardiovascular research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 64 citations in OpenAlex.
- Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis.Frontiers in cardiovascular medicine · 2021Pooled it
- Cyclic AMP-dependent regulation of ryanodine receptors in healthy and diseased hearts.Journal of molecular and cellular cardiology · 2026Review
- KFrontiers in physiology · 2025Article
- Calcium-mediated DAD in membrane potentials and triggered activity in atrial myocytes of ETV1Journal of cellular and molecular medicine · 2024Article
- Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis.Cardiovascular research · 2023Article
- Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads.Communications biology · 2023Article
- Role of CaArchives of toxicology · 2023Review
- Short peptide pharmacophores developed from protein phosphatase-1 disrupting peptides (PDPs).Bioorganic & medicinal chemistry · 2022Article
- Article
- MCU Overexpression Rescues Inotropy and Reverses Heart Failure by Reducing SR CaCirculation research · 2021Article
- Mechanisms underlying pathological CaPflugers Archiv : European journal of physiology · 2021Review
- The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation.Pflugers Archiv : European journal of physiology · 2021Review
- Cellular and mitochondrial mechanisms of atrial fibrillation.Basic research in cardiology · 2020Review
- Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target.Nature reviews. Cardiology · 2020Review
- Loss of SPEG Inhibitory Phosphorylation of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation.Circulation · 2020Article
- Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective.Circulation research · 2020Review
- Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia.Heart rhythm · 2020Article
- The Genetic Puzzle of Familial Atrial Fibrillation.Frontiers in cardiovascular medicine · 2020Review
- Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation.Circulation · 2019Article
- Role of type 2A phosphatase regulatory subunit B56α in regulating cardiac responses to β-adrenergic stimulation in vivo.Cardiovascular research · 2019Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
aimsAltered Ca(2+) handling in atrial fibrillation (AF) has been associated with dysregulated protein phosphatase 1 (PP1) and subcellular heterogeneities in protein phosphorylation, but the underlying mechanisms remain unclear. This is due to a lack of investigation into the local, rather than global, regulation of PP1 on different subcellular targets such as ryanodine receptor type 2 (RyR2), especially in AF. METHODS AND
resultsWe tested the hypothesis that impaired local regulation of PP1 causes RyR2 hyperphosphorylation thereby promoting AF susceptibility. To specifically disrupt PP1's local regulation of RyR2, we used the spinophilin knockout (Sp(-/-)) mice (Mus musculus) since PP1 is targeted to RyR2 via spinophilin. Without spinophilin, the interaction between PP1 and RyR2 was reduced by 64%, while RyR2 phosphorylation was increased by 43% at serine (S)2814 but unchanged at S2808. Lipid bilayer experiments revealed that single RyR2 channels isolated from Sp(-/-) hearts had an increased open probability. Likewise, Ca(2+) spark frequency normalized to sarcoplasmic reticulum Ca(2+) content was also enhanced in Sp(-/-) atrial myocytes, but normalized by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitors KN-93 and AIP and also by genetic inhibition of RyR2 S2814 phosphorylation. Finally, Sp(-/-) mice exhibited increased atrial ectopy and susceptibility to pacing-induced AF, both of which were also prevented by the RyR2 S2814A mutation.
conclusionPP1 regulates RyR2 locally by counteracting CaMKII phosphorylation of RyR2. Decreased local PP1 regulation of RyR2 contributes to RyR2 hyperactivity and promotes AF susceptibility. This represents a novel mechanism for subcellular modulation of calcium channels and may represent a potential drug target of AF.
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