p38α regulates SERCA2a function

cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile function. The aim of this study was to identify the mechanism mediating the positive inotropic effect of p38 inhibition. Isolated adult and neonatal cardiomyocytes and perfused rat hearts were utilized to investigate the molecular mechanisms regulated by p38. PLB phosphorylation was enhanced in cardiomyocytes by chemical p38 inhibition, by overexpression of dominant negative p38 alpha and by p38 alpha RNAi, but not with dominant negative p38 beta. Treatment of cardiomyocytes with dominant negative p38 alpha significantly decreased Ca2+-transient decay time indicating enhanced sarco/endoplasmic reticulum Ca2+-ATPase function and increased cardiomyocyte contractility. Analysis of signaling mechanisms involved showed that inhibition of p38 decreased the activity of protein phosphatase 2A, which renders protein phosphatase inhibitor-1 phosphorylated and thereby inhibits PP1. In conclusion, inhibition of p38 alpha enhances PLO phosphorylation and diastolic Ca2+ uptake. Our findings provide evidence for novel mechanism regulating cardiac contractility upon p38 inhibition. (C) 2013 Elsevier Ltd. All rights reserved.