Decoy peptides targeted to protein phosphatase 1 inhibit dephosphorylation of phospholamban in cardiomyocytes

Oh, Jae Gyun; Kim, Jihwa; Jang, Seung Pil; Nguen, Mai; Yang, Dong Kwon; Jeong, Dongtak; Park, Zee Yong; Park, Sung‐Gyoo; Hajjar, Roger J.; Park, Woo Jin

doi:10.1016/j.yjmcc.2012.12.005

Cited by 18 publications

(22 citation statements)

References 51 publications

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“…Therapeutic strategies include (a) decreasing PLB levels with micro RNA or antibodies (Andino et al 2008; He et al 1999), (b) increasing PLB phosphorylation by inhibiting PP1, the protein phosphatase that dephosphorylates PLB at both S16 and T17 (Fish et al 2013; Miyazaki et al 2012; Oh et al 2013; Pritchard et al 2013; Xu et al 2007; Zhang et al 2012), (c) uncoupling PLB and SERCA2a with drugs, (d) stabilizing the R state of PLB using drugs, (e) stabilizing the PLB pentamer, and (f) administering PLB loss-of-inhibition mutants using gene therapy.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

“…Gene therapy vectors that inhibit PP1 have successfully improved cardiac performance in animals (Fish et al 2013; Miyazaki et al 2012; Oh et al 2013; Pritchard et al 2013) .AAV9 delivery of PP1 inhibitor was cardioprotective in mice (Pritchard et al 2013). Intracoronary delivery of AAV9.I-1c to pigs after left anterior descending artery occlusion-induced heart failure stayed the progression of heart failure and reduced the size of the scar created by the myocardial infarction (Fish et al 2013).…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

“…Decoy peptides for PP1 have also been used to keep PLB phosphorylated. The decoy peptides include the 9 amino-acid PLB sequence 14-22 (which contains the phosphorylation sites S16 and T17), with and without phosphomimetic S16E or T17E mutations (Oh et al 2013). …”

Section: Therapeutic Strategiesmentioning

confidence: 99%

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Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

Ablorh

Thomas

2015

Biophys Rev

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We review the recent development of novel biochemical and spectroscopic methods to determine the site-specific phosphorylation, expression, mutation, and structural dynamics of phospholamban (PLB), in relation to its function (inhibition of the cardiac calcium pump, SERCA2a), with specific focus on cardiac physiology, pathology, and therapy. In the cardiomyocyte, SERCA2a actively transports Ca2+ into the sarcoplasmic reticulum (SR) during relaxation (diastole) to create the concentration gradient that drives the passive efflux of Ca2+ required for cardiac contraction (systole). Unphosphorylated PLB (U-PLB) inhibits SERCA2a, but phosphorylation at S16 and/or T17 (producing P-PLB) changes the structure of PLB to relieve SERCA2a inhibition. Because insufficient SERCA2a activity is a hallmark of heart failure, SERCA2a activation (by gene therapy (Andino et al. 2008; Fish et al. 2013; Hoshijima et al. 2002; Jessup et al. 2011) or drug therapy (Ferrandi et al. 2013; Huang 2013; Khan et al. 2009; Rocchetti et al. 2008; Zhang et al. 2012)) is a widely sought goal for treatment of heart failure. This review describes rational approaches to this goal. Novel biophysical assays, using site-directed labeling and high-resolution spectroscopy, have been developed to resolve the structural states of SERCA2a-PLB complexes in vitro and in living cells. Novel biochemical assays, using synthetic standards and multidimensional immunofluorescence, have been developed to quantitate PLB expression and phosphorylation states in cells and human tissues. The biochemical and biophysical properties of U-PLB, P-PLB, and mutant PLB will ultimately resolve the mechanisms of loss of inhibition and gain of inhibition to guide therapeutic development. These assays will be powerful tools for investigating human tissue samples from the Sydney Heart Bank, for the purpose of analyzing and diagnosing specific disorders.

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Section: Therapeutic Strategiesmentioning

confidence: 99%

Section: Therapeutic Strategiesmentioning

confidence: 99%

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Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

Ablorh

Thomas

2015

Biophys Rev

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“…A number of studies have shown that the inotropic effect of ISO is exerted through PKA-mediated phosphorylation of I-1 (38,39). In addition, I-1 becomes a potent inhibitor of PP1 when it is phosphorylated at Thr35 by PKA (40).…”

Section: Pkcαmentioning

confidence: 99%

SERCA2a: a prime target for modulation of cardiac contractility during heart failure

Park

Oh²

2013

BMB Reports

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Heart failure is one of the leading causes of sudden death in developed countries. While current therapies are mostly aimed at mitigating associated symptoms, novel therapies targeting the subcellular mechanisms underlying heart failure are emerging. Failing hearts are characterized by reduced contractile properties caused by impaired Ca2+ cycling between the sarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/endoplasmic reticulum Ca2+ATPase 2a (SERCA2a) mediates Ca2+ reuptake into the SR in cardiomyocytes. Of note, the expression level and/or activity of SERCA2a, translating to the quantity of SR Ca2+ uptake, are significantly reduced in failing hearts. Normalization of the SERCA2a expression level by gene delivery has been shown to restore hampered cardiac functions and ameliorate associated symptoms in pre-clinical as well as clinical studies. SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban, protein phosphatase 1, inhibitor-1, and PKCα. SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation. In this review, we will highlight the molecular mechanisms underlying the regulation of SERCA2a activity and the potential therapeutic modalities for the treatment of heart failure. [BMB Reports 2013; 46(5): 237-243]

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“…A complete phosphorylation profile for each age group, gender, and etiology of heart failure could aid diagnosis and guide rational design of disease-specific drug or gene therapies (25)(26)(27), targeted toward specific PLB phosphorylation states. Such a phosphorylation profile could also evaluate protein phosphatase-1, CaMKII, and PKA as targets for small molecules (28,29). Assessing the role of PLB phosphorylation states in cardiac pathology and treatment requires quantification of their concentrations and functions.…”

mentioning

confidence: 99%

Synthetic Phosphopeptides Enable Quantitation of the Content and Function of the Four Phosphorylation States of Phospholamban in Cardiac Muscle

Ablorh

Dong

James

et al. 2014

Journal of Biological Chemistry

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Background: Phosphorylation of phospholamban regulates cardiac calcium transport, but the content and function of the four phosphorylation states of phospholamban are unknown. Results: Synthetic phosphopeptides solved both problems. Conclusion:The phosphorylation states were quantified in normal and hypertrophic pig hearts, and each has a distinct effect on calcium transport. Significance: This information is needed for improved diagnosis and treatment of heart failure.

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Decoy peptides targeted to protein phosphatase 1 inhibit dephosphorylation of phospholamban in cardiomyocytes

Cited by 18 publications

References 51 publications

Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

SERCA2a: a prime target for modulation of cardiac contractility during heart failure

Synthetic Phosphopeptides Enable Quantitation of the Content and Function of the Four Phosphorylation States of Phospholamban in Cardiac Muscle

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