ABCD of the phosphodiesterase family: interaction and differential activity in COPD

Abstract

Phosphodiesterases (PDEs) are important enzymes that hydrolyze the cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. They are highly conserved across species and as well as their role in signal termination, they also have a vital role in intra-cellular localization of cyclic nucleotide signaling and integration of the cyclic nucleotide pathways with other signaling pathways. Because of their pivotal role in intracellular signaling, they are now of considerable interest as therapeutic targets in a wide variety diseases, including COPD where PDE inhibitors may have bronchodilator, anti-inflammatory and pulmonary vasodilator actions. This review examines the diversity and cellular localization of the isoforms of PDE, the known and speculative relevance of this to the treatment of COPD, and the range of PDE inhibitors in development together with a discussion of their possible role in treating COPD.

Figure 1

Schematic diagram of the domain structure of the eleven PDE families. Copyright © 2007. Adapted from with permission Conti M, Beavo J. 2007. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem, 76:481–511.

Figure 2

Schematic representation of the some of the complexes in which phosphodiesterases (PDEs) are involved in a hypothetical cell. Reprinted from with permission Conti M, Beavo J. 2007. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem, 76:481–511. Copyright © 2007. Annual Reviews www.annualreviews.org. Abbreviations: AC, adenylyl cyclase; AKAP, A kinase – anchoring proteins; βAR, arrestins; βAR2, adrenergic receptor 2; CFTR, cystic fibrosis transmembrane conductance regulator; CNGC, cyclic nucleotide gated channels; mit, mitochondria; PKA, protein kinase A; RyR, ryanodine receptors.

Figure 3

Schematic representation of human PDE4 subtypes and products of mRNA splice variants The number of amino acid (AA) residues in each protein appears to the right of the schematic diagram. Adapted and updated with permission from Torphy TJ. 1998. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med, 157:351–70. Copyright © 2008 American Thoracic Society. Abbreviation: UCR, upstream conserved region.