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

Tibbo, A. J. et al. (2022) Phosphodiesterase type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins. Journal of Molecular and Cellular Cardiology, 165, pp. 86-102. (doi: 10.1016/j.yjmcc.2022.01.001) (PMID:34999055)

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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.

Item Type:Articles
Additional Information:GSB is supported by BHF PG/17/26/32881 and AJT by the College of Veterinary, Medical and Life Sciences Doctoral training Programme. This work was supported by Agence Nationale de la Recherche (ANR-19-CE14-0038-02 to GV, ANR-16-CE14-0014 to DM) and Fédération Française de Cardiologie (to DM). We thank Dr. Ana-Maria Gomez for help with confocal Ca2+ imaging of sino-atrial node tissue. TB is supported by BHF (PG19/13/34247).
Glasgow Author(s) Enlighten ID:Tibbo, Dr Amy and Dobi, Ms Sara and Smith, Professor Godfrey and Tejeda, Dr Gonzalo and McFall, Dr Aisling and Ling, Miss Jiayue and Baillie, Professor George and MacLeod, Miss Ruth and Blair, Dr Connor and MacQuaide, Dr Niall and Smith, Dr Brian and Gok, Mr Caglar
Authors: Tibbo, A. J., Mika, D., Dobi, S., Ling, J., McFall, A., Tejeda, G. S., Blair, C., MacLeod, R., MacQuaide, N., Gök, C., Fuller, W., Smith, B. O., Smith, G. L., Vandecasteele, G., Brand, T., and Baillie, G. S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Journal of Molecular and Cellular Cardiology
ISSN (Online):1095-8584
Published Online:06 January 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Journal of Molecular and Cellular Cardiology 165: 86-102
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301414Targeting PDE3/4 to allow regulation of cardiac calcium homeostasis in diseaseGeorge BaillieBritish Heart Foundation (BHF)PG/17/26/32881CAMS - Cardiovascular Science