PDE3A may regulate myocardial Ca2+ cycling through interacting with SERCA2 in mouse heart

Abstract

Growing evidence indicates that cardiac functions, from contractility to chronic gene expression and cardiac structural remodeling, are regulated by multiple spatially, temporally, and functionally distinct pools of cAMP. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP and cGMP, regulate the amplitude, duration, and compartmentation of cAMP‐mediated signaling. PDE3 plays an important role in regulating cAMP metabolism in the cardiovascular system. Although PDE3 inhibitors, by raising cAMP, produce acute inotropic and vasodilatory effects, the mechanism for these actions are unclear. In our experiments, we found that PDE3A co‐localizes with SERCA2 and phospholamban during sucrose gradient centrifugation of mouse cardiac membranes. In addition, using LC‐MS/MS analysis of PDE3A immunoprecipitates, we found that PDE3A immunoprecipitated with sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2), which regulates Ca2+ uptake into intracellular stores. Immunoblot and enzyme activity assays also indicated that PDE3A immunoprecipitated with SERCA2, and other signaling molecules. These data suggest that, as a component of a SERCA2‐containing macromolecular complex, PDE3A regulates a discrete cAMP pool important in mediating some effects of SERCA2 on cardiac function. Compared with wild type mice, expression of SERCA2 and phosphorylation of phospholamban at Ser16 were increased in heart tissue from PDE3A‐/‐ mice, generated in our laboratory. Effects of PDE3A on Ca2+ cycling and ventricular function will be investigated in future studies.