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

J Mol Cell Cardiol. 2022 Apr:165:86-102. doi: 10.1016/j.yjmcc.2022.01.001. Epub 2022 Jan 6.


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.

Keywords: Action potential; Cyclic AMP; PDE4; POPDC1; Submitted as preprint on bioRxiv; TREK1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cyclic AMP* / metabolism
  • Cyclic AMP-Dependent Protein Kinases* / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Mice
  • Phosphoric Diester Hydrolases / metabolism
  • Second Messenger Systems
  • Signal Transduction


  • Carrier Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoric Diester Hydrolases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4A protein, human
  • Pde4a protein, mouse