ReviewKeynote review: Phosphodiesterase-4 as a therapeutic target
Section snippets
Functional significance of phosphodiesterase-4 isoforms
Cyclic nucleotide phosphodiesterases (PDEs) provide the only route for degrading cyclic AMP (cAMP), a key second messenger inside cells, thus providing a pivotal means of regulating cAMP levels. Their importance is emphasized by the multiplicity of cAMP-hydrolyzing PDEs, encoded by the human genome, and their high conservation between species and during the selective pressures of evolution. Of these, the multi-gene phosphodiesterase-4 (PDE4) family has attracted considerable attention over the
Catalyitic domain structure
The crystal structure of the apo catalytic domain of PDE4B [68] reveals a compact α-helical structure consisting of 16 helices divided into three subdomains (Figure 2a). The active site forms a deep pocket located at the junction of the three subdomains and is lined with highly conserved residues (Figure 2b). A binuclear metal ion center, where Zn2+ is coordinated by conserved, paired histidines and aspartates and two water molecules, is found at the wider side of the active site. Mg2+ is also
Effects of PDE4 inhibition in leukocytes
Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine that is produced largely by monocytes, macrophages and T cells, is an important drug target in rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and psoriasis. TNF-α production by peripheral blood monocytes and T cells is inhibited by rolipram [74, 75]. In monocytes this inhibition is accompanied by the elevation of intracellular cAMP and the activation of PKA, effects that are synergistically enhanced by the addition of
Conclusions
The plethora of PDE4 isoforms and their widespread expression pattern could be looked upon as a strength and a weakness of PDE4 as a target for drug development. A major challenge will be to refine PDE4 inhibitors to maximize therapeutic efficacy in specific disease states. Thus, future developments are probably going to focus on the ability to target specific PDE4 subfamilies and isoforms. By doing these structural analyses, PDEs are positioned to play a key role in the identification of
Acknowledgements
MDH thanks the Medical Research Council (UK) for financial support. KYJZ would like to thank his colleagues at Plexxikon for their generous support and stimulating discussions.
References (120)
Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling
J. Biol. Chem.
(2003)Compartmentalization of phosphodiesterases and protein kinase A: opposites attract
FEBS Lett.
(2005)- et al.
Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes
Curr. Opin. Cell Biol.
(2005) Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme
Neuropsychopharmacology
(2002)In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region
Cell. Signal.
(2005)- et al.
PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease
Trends Pharmacol. Sci.
(2004) Phosphodiesterase 4-selective inhibition: novel therapy for the inflammation of COPD
Pulm. Pharmacol. Ther.
(2005)- et al.
Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4)
Trends Pharmacol. Sci.
(2004) Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter
J. Biol. Chem.
(2002)Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclic AMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways. A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression in cells
J. Biol. Chem.
(2000)
Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation
J. Biol. Chem.
Short term feedback regulation of cAMP in FRTL-5 thyroid cells. Role of PDE4D3 phosphodiesterase activation
J. Biol. Chem.
ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases
The involvement of COOH-terminal docking sites and NH2-terminal UCR regions. J. Biol. Chem.
Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2
J. Biol. Chem.
Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase
J. Biol. Chem.
UCR1 and UCR2 domains unique to the cAMP-specific phosphodiesterase family form a discrete module via electrostatic interactions
J. Biol. Chem.
The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases
J. Biol. Chem.
Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases
Cell. Signal.
The human cyclic AMP-specific phosphodiesterase PDE-46 (HSPDE4A4B) expressed in transfected COS7 cells occurs as both particulate and cytosolic species that exhibit distinct kinetics of inhibition by the antidepressant rolipram
J. Biol. Chem.
Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition
J. Biol. Chem.
Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5
Cell. Signal.
The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform
J. Biol. Chem.
Crystal structure of phosphodiesterase 4D and inhibitor complex
FEBS Lett.
Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases
Structure
Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with amp 8-br-AMP, and rolipram
J. Mol. Biol.
TAPAS-1, a novel microdomain within the unique N-terminal region of the PDE4A1 cAMP-specific phosphodiesterase that allows rapid, Ca2+-triggered membrane association with selectivity for interaction with phosphatidic acid
J. Biol. Chem.
Phosphodiesterase 4D and protein kinase a type II constitute a signaling unit in the centrosomal area
J. Biol. Chem.
In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting
Cell. Signal.
The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3 Consequences for altered intracellular distribution
J. Biol. Chem.
The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase isoform confers preferential interaction with beta-arrestins
J. Biol. Chem.
Occupancy of the catalytic site of the PDE4A4 cyclic AMP phosphodiesterase by rolipram triggers the dynamic redistribution of this specific isoform in living cells through a cyclic AMP independent process
Cell. Signal.
A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases
Mol. Cell
Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity
Structure (Camb)
Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease
Lancet
Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity
J. Biol. Chem.
Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells
J. Biol. Chem.
cAMP-induced Interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation
J. Biol. Chem.
Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis
J. Invest. Dermatol.
Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium
J. Biol. Chem.
Protein kinase A associates with cystic fibrosis transmembrane conductance regulator via an interaction with ezrin
J. Biol. Chem.
E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells
J. Biol. Chem.
Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells
Blood
The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma
Blood
The novel long PDE4A10 cyclic AMP phosphodiesterase shows a pattern of expression within brain that is distinct from the long PDE4A5 and short PDE4A1 isoforms
Cell. Signal
Cell-type specific integration of cross-talk between extracellular signal-regulated kinase and cAMP signaling
Mol. Pharmacol.
Cyclic nucleotide research-still expanding after half a century
Nat. Rev. Mol. Cell Biol.
Localized effects of cAMP mediated by distinct routes of protein kinase A
Physiol. Rev.
Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system
Mol. Pharmacol.
PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization
Biochem. J.
Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases
Circ. Res.
Cited by (0)
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Miles D. Houslay
Miles Houslay is Gardiner Professor of Biochemistry at the University of Glasgow, UK. He obtained his first degree in Biochemistry at the University of Wales in Cardiff, UK and gained his PhD at the University of Cambridge, UK. He has held faculty positions at the Universities of Cambridge (UK) and Manchester (UK). He has been involved in cell signaling research since its inception. His current research interest is focused on the role of phosphodiesterase-4 isoforms in underpinning cyclic AMP compartmentalization and cross-talk processes and the potential for identifying novel therapeutic opportunities.
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Peter Schafer
Peter Schafer is Associate Director of Biology at Celgene in Summit, USA. He obtained his BS in Biological Chemistry from the University of Chicago, USA and his PhD in Biochemistry, Molecular Biology and Cell Biology from Northwestern University. He has conducted research at the R.W. Johnson Pharmaceutical Research Institute on the role of p38 MAP kinase in inflammation. His current efforts in drug discovery focus on PDE4 inhibitors, immunomodulation and angiogenesis.
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Kam Y.J. Zhang
Kam Zhang is Director of Structural Biology at Plexxikon in Berkeley, USA. He obtained his BS in Chemistry from Peking University, China and his PhD in Protein Crystallography from the University of York, UK. He has conducted research at UCLA, Fred Hutchinson Cancer Research Center and at Structural Genomix on crystallographic phasing, protein folding, apoptosis and crystallographic automation. His current work focuses on scaffold-based drug discovery for various therapeutic targets, including phosphodiesterases, using high throughput co-crystallography.