PDE4-Mediated cAMP Signalling

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”.

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…As production of cAMP is utilized by a variety of different Gs-coupled receptors to transduce signals, compartmentalization of signaling intermediates is crucial to define physiological outcomes specific to each receptor (249). This compartmentalization of cyclic nucleotide signaling is achieved by virtue of PDEs being tethered to a precise cellular location via binding partners (Table S1).…”

“…In the cardiovascular system, PDE2, PDE3 and PDE4 isoforms control different subcellular pools of cyclic nucleotides to regulate important cardiac functions from myocardial contraction/relaxation to chronic cell growth and survival, and disruption of this PDE signaling has been associated with disease (for review, see (1)). For example, heart failure has been associated with reduced levels of PDE3A and PDE4D, which results in myocyte apoptosis and cardiac arrhythmias, respectively (235,249).…”

Rolipram, a PDE4 Inhibitor, Enhances the Inotropic Effect of Rat Heart by Activating SERCA2a

“…The small, highly diffusible molecule, cAMP exerts multiple, discrete receptor-specific responses in the same cells (Fertig and Baillie, 2018). Such multiple responses of cAMP are based on compartmentalization of cAMP signaling by restricting the number and identity of PKA-phosphorylated substrates (Zaccolo and Pozzan, 2002) and the fine control by the subcellular localization of PDEs that degrade cAMP (Fertig and Baillie, 2018). Among the six PDE families which are expressed in the myocardium, PDE4 appears to be predominantly in the heart (Eschenhagen, 2013).…”

“…Among the six PDE families which are expressed in the myocardium, PDE4 appears to be predominantly in the heart (Eschenhagen, 2013). More than 20 isoforms belong to four different PDE4 genes, PDE4A, 4B, 4C, and 4D, with PDE4A, 4B, and 4D detected in the hearts (Kostic et al., 1997), with PDE4 and D5 interacting with β-arrestin (Bolger et al., 2003), PDE4B and 4D with the cardiac L-type Ca 2+ channel (Leroy et al., 2011), PDE4B with ryanodine receptor (RyR) (Fertig and Baillie, 2018), PDE4D with SERCA2a (Beca et al., 2011), PDE4D3 with slow delayed rectifier potassium current I KS channel (Terrenoire et al., 2009; Parks et al., 2014). The cellular integrated function of PDE4 is based on the distribution of the localized PDE4 subtypes and cAMP levels which are affected by adrenergic stimulation (Fertig and Baillie, 2018).…”

Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench

“…cAMP exerts its effect through effector proteins such as protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), cyclic nucleotide activated ion channels, and popeye domain containing proteins. (9) Importantly, the duration and amplitude of cAMP signaling are exclusively controlled by PDEs. Therefore, under pathological conditions, any changes in PDE expression could result in aberrant cAMP signaling.…”