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Protein Phosphatase 2A Maintains Calcium Homeostasis in the heart

【摘要】:正Intracellular Ca~(2+) is the central regulator in cardiac excitation-contraction coupling and modulation of cardiac gene expression.It is becoming increasingly apparent that alterations in myocyte Ca~(2+) regulation are critically important in both the mechanical dysfunction and arrhythmogenesis associated with congestive heart failure.During each cycle of excitation- contraction coupling,Ca~(2+) enters the cell through L-type Ca~(2+) channels(LTCC),which triggers the Ca~(2+) release from the sarcoplasmic reticulum through calcium release channel(RyR),and most of which is recycled by SR Ca -ATPase(SERCA2a).Previous study has demonstrated the indispensability of reversible phosphorylation regulation on the activity of those calcium handling proteins.However,it remains unclear the precise role of phosphatase in the regulation.In our study,mouse with a heart specific protein phosphatase Ca knockout developed dilated cardiomyopathy (DCM) in the ventricles and died soon after the ablation due to congestive heart failure.The development of DCM was correlated with electrophysiological remodeling in isolated ventricular moycytes,including a significant prolongation of APD_(90),increased L-type calcium currents(I_(Ca-L)),decreased transient outwards potassium currents(I_(to)).In consistence with changes in currents of I_(Ca-L),I_(to),an up-regulation of Cav1.2, pore-forming subunit of LTCC whereas down-regulations of Kv4.2,Kv4.3,Kv1.4 as well as KChIP2 proteins,which co-assemble transient outward K~+ channel conducting l_(to,f) and I_(to,s),respectively,were detected by immunoblot and real time-PCR analysis.In addition,remarkable increase in the phosphorylation level of Serine 1928 of alpha subunit for LTCC paralleled with up-regulated its protein expression was revealed by immunohistochemistry staining.The co-localization of PP2A Ca and Cav1.2, and their physical interactions were documented with immunocytochemistry and co-immunoprecipitation detection.Furthermore,the catalytic activity of PP2A on LTCC was directly addressed using in vitro kinase examination.Identification of up-regulation of phosphorylated RyR and IPP-1(an inhibitor of protein phosphatase 1 which controls the activity of SERCA2a through phospholamban ) demonstrated a potential mechanism for the overload of Ca~(2+) ions in the cardiomyocytes in probe marked assay by flow cytometry, which also provides an explanation for the disturbance of calcium ions flux in the cardiomyocytes of PP2A Ca K.O mice.In conclusion,our study shows that PP2A plays various roles in the regulation of calcium handling proteins through dephosphorylation,and is no doubt one of the key regulator for the maintenance of calcium homeostasis in the heart.

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