A Decoy Peptide Selectively Inhibiting Dephosphorylation of Phospholamban
- Authors
- Park, Woo Jin; Oh, Jae Gyun; Jeong, Dongtak; Hajjar, Roger J.
- Issue Date
- Aug-2012
- Publisher
- Lippincott Williams & Wilkins Ltd.
- Keywords
- Heart failure; Contractility; Phospholamban
- Citation
- Circulation Research, v.111, no.4
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- Circulation Research
- Volume
- 111
- Number
- 4
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/32199
- DOI
- 10.1161/res.111.suppl_1.a38
- ISSN
- 0009-7330
1524-4571
- Abstract
- Cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) plays a crucial role in Ca2+ handling in cardiomyocytes. Phospholamban (PLB) is an endogenous inhibitor of SERCA2a and its inhibitory activity is enhanced by dephosphorylation by protein phosphatase 1 (PP1). Therefore, blocking PP1-mediated dephosphorylation of PLB would be an efficient strategy for restoration of the reduced SERCA2a activity in failing hearts. We sought to develop a decoy peptide that mimics the phosphorylated PLB and thus competitively inhibits the PP1-mediated dephosphorylation of PLB. The phosphorylation sites, Ser16 and Thr17, are located within the flexible extra-membrane loop (amino acids 14-22) of PLB. We therefore synthesized a 9-mer pseudo-phosphorylated peptide derived from this region with a replacement of Ser16 with Glu (ψ-PLB-SE). Two other 9-mer peptides with wild type PLB sequence (ψ-PLB) or with a replacement of Ser16 with Ala (ψ-PLB-SA) were also synthesized. These peptides were coupled to a cell-permeable peptide TAT to facilitate cellular uptake. Treatment of adult rat cardiomyocytes with TAT-ψ-PLB-SE, but not with TAT-ψ-PLB or TAT-ψ-PLB-SA, significantly elevated the phosphorylation level of PLB, concomitant with an increase in contractile parameters in vitro. Perfusion of isolated rat hearts with TAT-ψ-PLB-SE significantly restored the left ventricular developed pressure that was suppressed by ischemia-reperfusion (Fig. 1). These data indicate that ψ-PLB-SE prevented dephosphorylation of PLB by acting as a decoy for PP1 and it would provide effective modality to regulate SERCA2a activity in failing hearts.
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