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J Cardiovasc Dev Dis
2018[Jan]; 5
(1
): ? PMID29385021
show ga
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 ?-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".
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