ArticleBasic research in cardiology2012
Constitutive phosphorylation of inhibitor-1 at Ser67 and Thr75 depresses calcium cycling in cardiomyocytes and leads to remodeling upon aging.
Article in Basic research in cardiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Heart Rhythm Harmony Becomes Discordant as We Age.Heart, lung & circulation · 2025Review
- Clinical neurocardiology: defining the value of neuroscience-based cardiovascular therapeutics - 2024 update.The Journal of physiology · 2025Review
- Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities.Nature communications · 2024Article
- Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Age-Related Cardiac Dysfunction: Hope for Better Aging?JACC. Basic to translational science · 2019Article
- Article
- Age-Dependent Protein Expression of Serine/Threonine Phosphatases and Their Inhibitors in the Human Cardiac Atrium.Advances in medicine · 2019Article
- Heterogeneity of adult masseter muscle satellite cells with cardiomyocyte differentiation potential.Experimental cell research · 2018Article
- Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity.Naunyn-Schmiedeberg's archives of pharmacology · 2017Article
- Chronic Contractile Dysfunction without Hypertrophy Does Not Provoke a Compensatory Transcriptional Response in Mouse Hearts.PloS one · 2016Article
- Counteracting Protein Kinase Activity in the Heart: The Multiple Roles of Protein Phosphatases.Frontiers in pharmacology · 2015Review
- Obesity does not lead to imbalance between myocardial phospholamban phosphorylation and dephosphorylation.Arquivos brasileiros de cardiologia · 2014Article
- Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca(2+) signaling.American journal of physiology. Heart and circulatory physiology · 2014Article
- Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation.Basic research in cardiology · 2014Article
- Targeted ablation of the histidine-rich Ca(2+)-binding protein (HRC) gene is associated with abnormal SR Ca(2+)-cycling and severe pathology under pressure-overload stress.Basic research in cardiology · 2013Article
- AAV9.I-1c delivered via direct coronary infusion in a porcine model of heart failure improves contractility and mitigates adverse remodeling.Circulation. Heart failure · 2013Article
- Impaired left ventricular function in the presence of preserved ejection in chronic hypertensive conscious pigs.Basic research in cardiology · 2012Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
The activity of protein phosphatase-1 (PP1) inhibitor-1 (I-1) is antithetically modulated by the cAMP-protein kinase A (PKA) and Ca(2+)-protein kinase C (PKC) signaling axes. β-adrenergic (β-AR) stimulation results in PKA-phosphorylation of I-1 at threonine 35 (Thr35) and depressed PP1 activity, while PKC phosphorylation at serine 67 (Ser67) and/or Thr75 increases PP1 activity. In heart failure, pThr35 is decreased while pSer67 and pThr75 are elevated. However, the role of Ser67/Thr75 phosphorylation in vivo and its effects on Ca(2+)-cycling are not known. Thus, our aim was to investigate the functional significance of Ser67 and Thr75 phosphorylation in intact hearts. We generated transgenic mice (TG) with cardiac-specific overexpression of constitutively phosphorylated I-1 at Ser67 and Thr75 (S67D/T75D) and evaluated cardiac function. The S67D/T75D cardiomyocytes exhibited significantly depressed Ca(2+)-kinetics and contractile parameters, compared with wild-type (WT) cells. The decreased Ca(2+)-cycling was associated with a 27 % increase in PP1 activity, no alterations in PP2 activity and impaired phosphorylation of myosin-binding protein-C (MyBPC). Upon aging, there was cardiac remodeling associated with increases in systolic and diastolic left ventricular internal diameter dimensions (at 16 months), compared with WTs. The results indicate that phosphorylation of I-1 at Ser67 and Thr75 is associated with increased PP1 activity and depressed cardiomyocyte Ca(2+)-cycling, which manifests in geometrical alterations over the long term. Thus, hyperphosphorylation of these sites in failing hearts may contribute to deteriorative remodeling.
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