Abstract 19852: PDE3A Binds Directly to and Inhibits SERCA2 Activity Independently of its Catalytic Activity

Introduction: SERCA2 controls cardiac contractility, and its activity is negatively regulated by the cAMP phosphodiesterase PDE3A through an unknown mechanism. Several preclinical trials have shown upregulation of SERCA2 gene therapy as beneficial in heart failure, but no specific SERCA2 activating agents have been reported. Hypothesis: We propose that PDE3A is physically associated with SERCA, and that this interaction regulates SERCA2 activity independent of the cAMP-degrading properties of PDE3A.We also wanted to evaluate whether this protein-protein interaction represent a novel drug target to increase SERCA2 activity in heart failure. Methods and Results: SERCA2 activity in PDE3A-transefected HEK293 vesicles was reduced compared to control. PDE3A also reduced SERCA2 activity in the presence of the PDE3A inhibitor Cilostamide, showing that PDE3A inhibits SERCA2 independently of its catalytic effect. A combination of immunoprecipitation and peptide interaction experiments revealed interaction between s...