Identification and characterization of proteins in sarcoplasmic reticulum from normal and failing human left ventricles

Movsesian, Matthew A.; Leveille, Cynthia J.; Krall, John M.; Colyer, John; Wang, Jerry H.; Campbell, Kevin P.

doi:10.1016/0022-2828(90)90990-j

Cited by 20 publications

(9 citation statements)

References 34 publications

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“…Further insights into the role of PP1 during heart failure were made through animal studies using Tg mice. Cardiac-specific overexpression of PP1 in Tg mice leads to cardiac dysfunction, dilated cardiomyopathy, and premature mortality, which are associated with decreases in the phosphorylation of PLN (34). As shown above, inhibiting PP1-mediated dephosphorylation of PLN can be an efficient strategy to activate SERCA2a.…”

Section: Protein Phosphatase 1/inhibitor-1mentioning

confidence: 90%

“…Ablation of I-1 results in increased PP1 activity and decreased phosphorylation of PLN. Moreover, basal cardiac functions are severely depressed in I-1 KO mice (34). In contrast, overexpression of I-1 in heart tissue engineered from neonatal rat cardiomyocytes or adult rat cardiomyocytes results in increased cell shortening and a concomitant increase in PLN phosphorylation (35).…”

Section: Protein Phosphatase 1/inhibitor-1mentioning

confidence: 99%

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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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Section: Protein Phosphatase 1/inhibitor-1mentioning

confidence: 90%

Section: Protein Phosphatase 1/inhibitor-1mentioning

confidence: 99%

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

Park

Oh²

2013

BMB Reports

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“…The components of the canine cardiac SR have been identified and characterised. Prominent among these are a 105kD Ca 2+ -ATPase, phospholamban of approximately 27-29kD, a 55kD calsequestrin, two glycoproteins of 130kD and 53kD and a high molecular weight ryanodine receptor of >400kD (19). Species differences in protein components are very prominent in SR samples.…”

Section: Discussionmentioning

confidence: 99%

“…Species differences in protein components are very prominent in SR samples. Rabbit skeletal, canine and human cardiac SR samples, when run simultaneously (19), showed varied differences in banding pattern. Human cardiac SR samples show many more bands in the region between 97.4kD and 45kD than its canine cardiac counterpart.…”

Section: Discussionmentioning

confidence: 99%

Caprine cardiac sarcoplasmic reticulum isolation and biochemical characterisation with emphasis on Ca2+-adenosine triphosphatase

D’Souza

Ashavaid

2007

Indian J Clin Biochem

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“…Ca 2+ accumulation by the cardiac SR occurs through the activity of SERCA2, a 105‐kDa Ca 2+ ‐ and Mg 2+ ‐dependent ATPase that transports Ca 2+ from the cytosol into the lumen of the sarcoplasmic reticulum. 1 The large amounts of Ca 2+ released from the SR initiate the cross‐bridge interaction and thereby an increase in force of contraction. It is important to appreciate, therefore, that SERCA2 activity determines not only the rate and extent of relaxation, but also the rate and amplitude of contraction, since these are determined by the amount of Ca 2+ sequestered by the sarcoplasmic reticulum and the Ca 2+ gradient between the sarcoplasmic reticulum and the cytosol at the time that the Ca 2+ release occurs.…”

mentioning

confidence: 99%

cAMP‐Dependent Protein Kinase A‐Stimulated Sarcoplasmic Reticulum Function in Heart Failure^a

Schwinger

Bölck

Münch

et al. 1998

Annals of the New York Academy of Sciences

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It is unclear whether decreased protein expression of SERCA2 (SR-Ca(2+)-ATPase) and phospholamban (PLB), or alterations in the phosphorylation state of PLB leading to increased inhibition of SERCA2 are responsible for the reduced SERCA2 function in failing human myocardium. In crude membrane preparations from patients with terminal heart failure due to idiopathic dilated cardiomyopathy (DCM) and control hearts (NF), SERCA2 activity was measured with a NADH coupled assay. Protein expression of SERCA2 and PLB and the phosphorylation state at the two phosphorylation sites, serine-16-PLB and threonine-17-PLB, were investigated with specific (phosphorylation) antibodies and Western blot technique. In NF, the Vmax and the Ca2+ sensitivity of SERCA2 activity were significantly higher compared to DCM. Protein expression of SERCA2 and PLB were unchanged, whereas the phosphorylation status at both serine-16-PLB and threonine-17-PLB were significantly reduced in DCM. The native phosphorylation status of PLB measured by the back-phosphorylation technique was reduced in DCM as well. After stimulation with protein kinase A only the Ca2+ sensitivity, but not Vmax, increased. The reduced phosphorylation state of PLB may lead to decreased Ca2+ sensitivity of SERCA2 in failing human myocardium. The altered regulation of the SR-CA(2+)-ATPase in human heart failure may offer an opportunity for an improvement in the therapy of heart failure.

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Identification and characterization of proteins in sarcoplasmic reticulum from normal and failing human left ventricles

Cited by 20 publications

References 34 publications

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

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

Caprine cardiac sarcoplasmic reticulum isolation and biochemical characterisation with emphasis on Ca2+-adenosine triphosphatase

cAMP‐Dependent Protein Kinase A‐Stimulated Sarcoplasmic Reticulum Function in Heart Failure^a

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Identification and characterization of proteins in sarcoplasmic reticulum from normal and failing human left ventricles

Cited by 20 publications

References 34 publications

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

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

Caprine cardiac sarcoplasmic reticulum isolation and biochemical characterisation with emphasis on Ca2+-adenosine triphosphatase

cAMP‐Dependent Protein Kinase A‐Stimulated Sarcoplasmic Reticulum Function in Heart Failurea

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cAMP‐Dependent Protein Kinase A‐Stimulated Sarcoplasmic Reticulum Function in Heart Failure^a