Abstract Body (Do not enter title and authors here): Heart failure is a leading cause of death in the United States, and is associated with significant myocardial deterioration. cAMP and cGMP play critical roles in cardiovascular biology and disease. cAMP and cGMP form multiple spatially discrete and functionally distinct cyclic nucleotide 'pools,' each associated with unique multi-protein complexes comprising cyclases, PDEs, and other signaling molecules, contributing to distinct biological functions. Phosphodiesterase 10A (PDE10A) is able to hydrolyze both cAMP and cGMP. Our previous published study provides strong evidence supporting a critical role of PDE10A induction in pathological cardiac remodeling and suggest the therapeutic potential of PDE10A inhibition. However, the cellular and molecular mechanisms and the sources of cyclic nucleotides that are regulated by PDE10A remain unknown. Our encouraging results revealed that the anti-hypertrophic effect of PDE10A inhibition/deficiency is dependent on cAMP/PKA signaling in cultured adult mouse cardiomyocytes (CM). We identified the existence of adenosine-dopamine receptor (A_2AR-D₂R) heterodimer and the connection of PDE10A with A_2AR-D₂R signaling, by which PDE10A inhibition uniquely promotes heterodimerization of A_2AR-D₂R, and biased activation of D₂R/β-arrestin2 (βarr2) through A_2AR/cAMP/PKA-mediated phosphorylation of D₂R in CMs. Consistent with what we found in CM, disruption of A_2AR-D₂R heterodimer or D₂R/ βarr2-biased activation significantly abolish the protective effects of PDE10A inhibition on cardiomyopathy and dysfunction in vivo. Additionally, we found that activation of D₂R/βarr2 signaling attenuates stress-induced cardiac remodeling and dysfunction in vivo. Together, these results strongly suggest that PDE10A plays a critical role in pathological cardiac remodeling by promoting CM hypertrophy through regulation of A_2AR-D₂R/βarr2 biased signaling. Targeting PDE10A and GPCR heterodimerization in CMs may represent a novel therapeutic strategy for treating cardiac diseases.