Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene-related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways. Therefore, the investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies. This manuscript (i) overviews the different PDEs including their endogenous regulations and their specific inhibitors; (ii) analyses the intracellular implications of PDEs in regulating signalling cascades in pathogenesis, exemplified by two diseases affecting cell cycle and proliferation; and (iii) discusses perspectives for future therapeutic developments.

Figure 1

Intracellular targets for cAMP and cGMP.

Figure 2

PDE participation in the control of cell cycle. (A) Primary cultured HUVECs. (B) Jurkat cell line.

Figure 3

Participation of PDEs in intracellular signalling network: potential therapeutic implications. Local cAMP and cGMP levels controlled by PDEs activate PKA, PKG, CNGC and bind to GAF domains. PDE themselves interact with AKAP and other critical intracellular proteins. These two modes of interaction potentially participate in various diseases.