Next Article in Journal / Special Issue
Epac Function and cAMP Scaffolds in the Heart and Lung
Previous Article in Journal / Special Issue
Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System
Article Menu

Export Article

Open AccessFeature PaperReview
J. Cardiovasc. Dev. Dis. 2018, 5(1), 8; https://doi.org/10.3390/jcdd5010008

PDE4-Mediated cAMP Signalling

University of Glasgow, Glasgow G12 8QQ, UK
*
Author to whom correspondence should be addressed.
Received: 19 December 2017 / Revised: 18 January 2018 / Accepted: 23 January 2018 / Published: 31 January 2018
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
View Full-Text   |   Download PDF [1241 KB, uploaded 31 January 2018]   |  

Abstract

cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of these enzymes, PDE4, is particularly important in the cardiovascular system, where it has been extensively studied and shown to orchestrate complex, localised signalling that underpins many crucial functions of the heart. In the cardiac myocyte, cAMP activates PKA, which phosphorylates a small subset of mostly sarcoplasmic substrate proteins that drive β-adrenergic enhancement of cardiac function. The phosphorylation of these substrates, many of which are involved in cardiac excitation-contraction coupling, has been shown to be tightly regulated by highly localised pools of individual PDE4 isoforms. The spatial and temporal regulation of cardiac signalling is made possible by the formation of macromolecular “signalosomes”, which often include a cAMP effector, such as PKA, its substrate, PDE4 and an anchoring protein such as an AKAP. Studies described in the present review highlight the importance of this relationship for individual cardiac PKA substrates and we provide an overview of how this signalling paradigm is coordinated to promote efficient adrenergic enhancement of cardiac function. The role of PDE4 also extends to the vascular endothelium, where it regulates vascular permeability and barrier function. In this distinct location, PDE4 interacts with adherens junctions to regulate their stability. These highly specific, non-redundant roles for PDE4 isoforms have far reaching therapeutic potential. PDE inhibitors in the clinic have been plagued with problems due to the active site-directed nature of the compounds which concomitantly attenuate PDE activity in all highly localised “signalosomes”. View Full-Text
Keywords: phosphodiesterase 4; cardiac myocyte; vascular endothelium phosphodiesterase 4; cardiac myocyte; vascular endothelium
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Fertig, B.A.; Baillie, G.S. PDE4-Mediated cAMP Signalling. J. Cardiovasc. Dev. Dis. 2018, 5, 8.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
J. Cardiovasc. Dev. Dis. EISSN 2308-3425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top