Phosphodiesterase type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins

Cyclic AMP is a ubiquitous second messenger used to transduce intracellular signals from a variety of Gs-coupled receptors. Compartmentalisation of protein intermediates within the cAMP signaling pathway underpins receptor-specific responses. The cAMP effector proteins protein-kinase A and EPAC are found in complexes that also contain phosphodiesterases whose presence ensures a coordinated cellular response to receptor activation events. Popeye domain containing (POPDC) proteins are the most recent class of cAMP effectors to be identified and have crucial roles in cardiac pacemaking and conduction. We report the first observation that POPDC proteins exist in complexes with members of the PDE4 family in cardiac myocytes. We show that POPDC1 preferentially binds the PDE4A sub-family via a specificity motif in the PDE4 UCR1 region and that PDE4s bind to the Popeye domain of POPDC1 in a region known to be susceptible to a mutation that causes human disease. Using a cell-permeable disruptor peptide that displaces the POPDC1-PDE4 complex we show that PDE4 activity localized to POPDC1 modulates cycle length of spontaneous Ca2+ transients firing in intact mouse sinoatrial nodes. [Display omitted] •POPDC1 forms a complex with type 4 phosphodiesterases (PDE4s) in cardiac myocytes.•POPDC1 binds PDE4 enzymes in the Upstream Conserved Region 1 (UCR1) domain.•The PDE4 binding motif within the Popeye domain lies in a region that harbours a mutation, which underpins human disease.•Disruption of the POPDC1-PDE4 complex modulates the cycle length of spontaneous Ca2+ transients in the sinoatrial node.•Disruption of the POPDC1-PDE4 complex causes a significant prolongation of the action potential repolarization phase.