Inhibitors of cyclic nucleotide phosphodiesterase (PDE) PDE3A increase cardiac contractility in patients with heart failure, but their long-term use increases mortality. Two isoforms expressed in cardiac myocytes, PDE3A1 and PDE3A2, have amino acid sequences that are identical except for a unique N-terminal extension in PDE3A1. We found that PDE3A1 and PDE3A2 are selectively phosphorylated at alternative sites in response to the activation of PKA and PKC, respectively, resulting in differential regulation of their catalytic activity and protein interactomes. Existing PDE3 inhibitors thus target at least two functionally distinct cardiac isoforms likely with different roles in intracellular signaling. This raises the possibility that isoform-selective targeting may increase contractility in failing hearts without increasing mortality, providing a potential route for developing therapeutics
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