Abstract 190: Protein Phosphatase 2Ce Is a Novel Phospholamban Phosphatase that Exacerbates Cell Death and Suppresses Cardiac Contractility
Regulation of sarcoplasmic reticulum (SR) calcium-ATPase (SERCA) activity is critical for calcium homeostasis in cardiomyocytes, and has a major impact on contractility and cellular viability of cardiomyocytes. The key regulators for SERCA activity include protein kinases, cAMP dependent protein kinase A and calcium/calmodulin dependent protein kinase II, and protein phosphatase 1. In this report, we have discovered that protein phosphatase 2Ce (PP2Ce) is a novel serine/threonine protein phosphatase specifically targeted to SR membrane in cardiomyocytes. PP2Ce was detected to interact with phosphlamban in heart. Recombinant PP2Ce protein showed a potent and specific activity towards the calcium/calmodulin dependent protein kinase II dependent phospholamban phosphorylation at threonin 17 site with no significant activity to cAMP dependent protein kinase A dependent phospholamban phosphorylation at serine 16 site. Expression of PP2Ce blunted β-adrenergic stimulated increase of phospholamban phosphorylation without affecting phosphorylation of ryanodine recepter or troponin I. PP2Ce expression reduced β-adrenergic stimulated intracellular calcium transient in isolated adult rabbit ventricular myocytes, and promoted hydrogen peroxide induced cell death in cultured neonatal rat ventricular myocytes. Transgenic mice with cardiac specific expression of PP2Ce showed no significant basal phenotype. However, in isolated perfusion heart preparation, β-adrenergic stimulated contractility was significant reduced in PP2Ce transgenic hearts comparing to wild type controls. Furthermore, we observed significantly larger infarct sizes and more impaired functional recovery following global ischemia/reperfusion injury in the transgenic hearts comparing to wild type controls. Therefore, PP2Ce is a novel component of SR calcium regulatory network that has a potentially important role in cell death regulation and cardiac contractility.
- © 2012 by American Heart Association, Inc.