Cyclic nucleotide phosphodiesterases (PDEs): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals

Abstract

The cyclic nucleotide second messengers cAMP and cGMP each affect virtually all cellular processes. Although these hydrophilic small molecules readily diffuse throughout cells, it is remarkable that their ability to activate their multiple intracellular effectors is spatially and temporally selective. Studies have identified a critical role for compartmentation of the enzymes which hydrolyse and metabolically inactivate these second messengers, the PDEs (cyclic nucleotide phosphodiesterases), in this specificity. In the present article, we describe several examples from our work in which compartmentation of selected cAMP- or cGMP-hydrolysing PDEs co-ordinate selective activation of cyclic nucleotide effectors, and, as a result, selectively affect cellular functions. It is our belief that therapeutic strategies aimed at targeting PDEs within these compartments will allow greater selectivity than those directed at inhibiting these enzymes throughout the cells.

The safety and efficacy of Avanafil, a new 2ndgeneration PDE5i: comprehensive review and meta-analysis

“…PDE5 is only one of the members of a broader family of PDE, including at least 11 members. [8] The PDE5 shares the greatest similarities with PDE6 over any other family in terms of both amino acid sequences and biochemical and pharmacological properties. Transient, mild visual disturbances associated with sildenafil are related to inhibition of the photoreceptor PDE6, which hydrolyzes cGMP and is almost exclusively expressed in the retina.…”

“…Hence, selectivity is another key point to decrease side effects. [8] Other common side effects related to all PDE5i include headache, flushing, back pain, nasal congestion, and tachycardia, whereas serious events are extremely rare. [8] Although not life-threatening, these adverse events can be extremely bothersome and contribute to PDE5i discontinuation.…”

“…[8] Other common side effects related to all PDE5i include headache, flushing, back pain, nasal congestion, and tachycardia, whereas serious events are extremely rare. [8] Although not life-threatening, these adverse events can be extremely bothersome and contribute to PDE5i discontinuation. [7] Despite the huge amount of data, identification of the specific reasons underlying the high dropout rate in patients treated with first-generation PDE5is may be difficult, mostly because evidence-based studies are lacking.…”

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

“…Compartmentalization of specific sets of cAMP signal transducers and effector systems permits activation and regulation of individual signaling pathways, as well as propagation of specific downstream signals and biological responses At the molecular level, specific PDEs or subsets of PDEs contribute to this compartmentalization by their permanent or reversible recruitment to different subcellular locations where they are incorporated into different macromolecular cyclic nucleotide signaling complexes or signalosomes (summarized in Table ). In these signalosomes, PDEs assume specific functional roles by regulating distinct cyclic nucleotide signaling pathways at these different subcellular locations (Francis et al , ; Maurice et al , ,b). Mechanistically, individual PDEs, in an isoform‐specific manner, are targeted to different subcellular locations via their interactions with cellular structural elements and organelles such as lipid rafts and caveolae, with molecular scaffolds such as A‐kinase anchoring proteins (AKAPs), β ‐arrestin, or receptor for activated C‐kinase‐1 (RACK‐1), or with other adaptor complexes or regulatory partners, including Epacs.…”

“…These binding interactions are highly regulated and reversible. These compartmentalized signalosomes contain PDEs together with pathway‐specific regulators and effectors, as well as different proportions of cyclic nucleotide effectors, including adenylyl cyclases, PKA and PKG and other kinases, Epacs, phosphoprotein phosphatases, AKAPs, and/or other scaffold proteins (Table represents a partial list of PDE‐containing signalosomes, with scaffold proteins, known interacting partners, and presumed function) (Houslay et al , ; Tsai and Kass, ; Keravis and Lugnier, ; Francis et al , ; Maurice et al , ,b). Incorporation of individual PDEs into specific signalosomes regulates specificity of signal transduction in two ways: by tight temporal and spatial regulation of cyclic nucleotide concentrations and gradients within specific compartments and by preventing diffusion of signals into neighboring compartments.…”