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

Amy J. Tibbo, Delphine Mika, Sara Dobi, Jiayue Ling, Aisling McFall, Gonzalo S. Tejeda, Connor Blair, Ruth MacLeod, Niall MacQuaide, Caglar Gök, William Fuller, Brian O. Smith, Godfrey L. Smith, Grégoire Vandecasteele, Thomas Brand, George S. Baillie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

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 thePDE4 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 POPDC1modulates cycle length of spontaneous Ca2+ transients firing in intact mouse sinoatrial nodes.

Original languageEnglish
Pages (from-to)86-102
Number of pages17
JournalJournal of molecular and cellular cardiology
Volume165
Early online date5 Jan 2022
DOIs
Publication statusPublished - 1 Apr 2022

Keywords

  • POPDC1
  • PDE4
  • Cyclic AMP
  • Action potential
  • TREK1

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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