Modulation of Compartmentalised Cyclic Nucleotide Signalling via Local Inhibition of Phosphodiesterase Activity.

Marcella Brescia,Manuela Zaccolo

doi:10.3390/ijms17101672

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that degrade the cyclic nucleotides cAMP and cGMP, and play a key role in modulating the amplitude and duration of the signal delivered by these two key intracellular second messengers. Defects in cyclic nucleotide signalling are known to be involved in several pathologies. As a consequence, PDEs have long been recognized as potential drug targets, and they have been the focus of intense research for the development of therapeutic agents. A number of PDE inhibitors are currently available for the treatment of disease, including obstructive pulmonary disease, erectile dysfunction, and heart failure. However, the performance of these drugs is not always satisfactory, due to a lack of PDE-isoform specificity and their consequent adverse side effects. Recent advances in our understanding of compartmentalised cyclic nucleotide signalling and the role of PDEs in local regulation of cAMP and cGMP signals offers the opportunity for the development of novel strategies for therapeutic intervention that may overcome the current limitation of conventional PDE inhibitors.

Highlights

Introduction to Cyclic NucleotidesSignificant progress has been made since 1958, when Rall and Sutherland first described the involvement of adenosine 3 -5 -cyclic monophosphate in the cellular response to hormones [1,2]
This activation occurs by the binding of a first messenger to G protein-coupled receptors (GPCR), which triggers the release of the Gs α-subunit from the heterotrimeric G protein complex
The Gs α-subunit activates transmembrane adenylyl cyclases (ACs) for the generation of cAMP by the conversion of ATP [2]. cAMP can be generated by a soluble adenylyl cyclase. sAC is distinct from tmACs, as it is regulated by bicarbonate and Ca2+ and is present in the cytosol and in several intracellular organelles and structures [6]

Summary

Introduction to Cyclic Nucleotides

Significant progress has been made since 1958, when Rall and Sutherland first described the involvement of adenosine 3 -5 -cyclic monophosphate (cAMP) in the cellular response to hormones [1,2]. Binding of cGMP to PDE2 and PDE5 GAF domains increases the hydrolytic activity of the enzyme. This is interesting, as it allows cross-talk between the cAMP and cGMP pathways with possible reciprocal regulation. CGMP binding to PDE5 promotes PKG-mediated phosphorylation, which again increases PDE5 enzymatic activity This PDE5 regulatory mechanism does not seem to be cGMP-specific, as PKA-mediated phosphorylation appears to have a similar effect [17,19,20]. The regulation of PDE3 is involved in the interconnection between cAMP and cGMP signalling This enzyme has dual-specificity and binds with high affinity both cAMP and cGMP, which are mutually competitive substrates. Sci. 2016, 17, 1672 above differentially regulates the activity of the multiplicity of PDE isoforms and provides a means to fine-tuning CN levels in response to the continuously changing requirements of the cell [22,23]

Compartmentalisation of Cyclic Nucleotides

Local Inhibition of Phosphodiesterase Activity

Conclusions