Keynote review: Phosphodiesterase-4 as a therapeutic target
TL;DR: The range of PDE4 isoforms, their role in signaling, their structural biology and related preclinical and clinical pharmacology are delineated, to provide potential, novel therapeutics for the treatment of inflammatory diseases and psoriasis.
About: This article is published in Drug Discovery Today.The article was published on 2005-11-15. It has received 600 citations till now. The article focuses on the topics: PDE4B.
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TL;DR: Pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual P DEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.
Abstract: Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.
630 citations
TL;DR: It is demonstrated that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.
540 citations
Cites background from "Keynote review: Phosphodiesterase-4..."
...Rolipram is a potent, highly selective inhibitor of PDE4, the enzyme that specifically catalyzes the hydrolysis of cAMP (Houslay et al., 2005), a second messenger in most neuromodulatory systems in the brain....
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...Fourth, PDE4 isoforms are now well recognized as underpinning compartmentalized cAMP signaling (Di Benedetto et al., 2006) through being tethered to specific scaffold proteins such as barrestin and RACK1 (Houslay et al., 2005)....
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...…University of Glasgow, Glasgow G12 8QQ, United Kingdom 6University of Toronto, Departments of Medical Biophysics and Molecular & Medical Genetics, Toronto, ON M5S 1A1, Canada *Correspondence: mail.steve@btinternet.com (S.J.C.), david.porteous@ed.ac.uk (D.J.P.) DOI 10.1016/j.neuron.2007.04.015...
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TL;DR: Apremilast was effective in moderate to severe plaque psoriasis and no new significant adverse events emerged with continued ap Remilast exposure versus the placebo-controlled period.
Abstract: Background Apremilast works intracellularly to regulate inflammatory mediators. Objective ESTEEM 1 evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque psoriasis. Methods This phase III, multicenter, double-blind, placebo-controlled study randomized adults (2:1) to apremilast or placebo. At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Binary end points were analyzed using χ 2 test; continuous end points used analysis of covariance. Results In all, 844 patients were randomized (n = 282, placebo; n = 562, apremilast). At week 16, significantly more patients taking apremilast achieved 75% or greater reduction from baseline Psoriasis Area and Severity Index score (PASI-75) (33.1%) versus placebo (5.3%, P Limitations Data were limited to 52 weeks and may not generalize to nonplaque psoriasis. Conclusions Apremilast was effective in moderate to severe plaque psoriasis.
468 citations
Cites background from "Keynote review: Phosphodiesterase-4..."
...Cyclic adenosine monophosphate, a key modulator of immune cell responses, is predominantly regulated by phosphodiesterase 4 (PDE4).(1) Apremilast, an oral PDE4 inhibitor, works intracellularly to regulate inflammatory mediators, including pathways relevant to the pathogenesis of psoriasis....
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TL;DR: Genes for these important regulatory enzymes are linked to schizophrenia, stroke and asthma, thus indicating the therapeutic potential that selective inhibitors could have as anti-inflammatory, anti-depressant and cognitive enhancer agents.
403 citations
TL;DR: The current state of the art in the burgeoning field of phosphodiesterase pharmacology in the CNS is reviewed, with a focus on the treatment of psychiatric and neurodegenerative disorders.
Abstract: The therapeutic and commercial success of phosphodiesterase 5 inhibitors such as Viagra, Levitra and Cialis has sparked renewed interest in the phosphodiesterases as drug discovery targets. Virtually all the phosphodiesterases are expressed in the CNS, making this gene family a particularly attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders. Significantly, all neurons express multiple phosphodiesterases, which differ in cyclic nucleotide specificity, affinity, regulatory control and subcellular compartmentalization. Therefore, phosphodiesterase inhibition represents a mechanism through which it could be possible to precisely modulate neuronal activity. In this article, we review the current state of the art in the burgeoning field of phosphodiesterase pharmacology in the CNS.
390 citations
References
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TL;DR: Research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor–effector coupling, protein-kinase cascades and downregulation of drug responsiveness.
Abstract: Since the discovery in 1957 that cyclic AMP acts as a second messenger for the hormone adrenaline, interest in this molecule and its companion, cyclic GMP, has grown Over a period of nearly 50 years, research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor-effector coupling, protein-kinase cascades and downregulation of drug responsiveness The breadth and impact of this work is reflected by five different Nobel prizes
845 citations
TL;DR: Targeting of PKA and integration of a wide repertoire of proteins involved in signal transduction into complex signal networks further increase the specificity required for the precise regulation of numerous cellular and physiological processes.
Abstract: Tasken, Kjetil, and Einar Martin Aandahl. Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A. Physiol Rev 84: 137–167, 2004; 10.1152/physrev.00021.2003.—More than 20% of the ...
763 citations
TL;DR: PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments, and the recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity.
Abstract: cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMP-specific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins ('AKAPs') and receptor for activated C kinase 1 ('RACK1'), and, in the case of isoform PDE4A1, by a specific interaction (TAPAS-1) with phosphatidic acid. PDE4 isoforms are 'designed' to be regulated by extracellular-signal-related protein kinase (ERK), which binds to anchor sites on the PDE4 catalytic domain that it phosphorylates. The upstream conserved region 1 (UCR1) and 2 (UCR2) modules that abut the PDE4 catalytic unit confer regulatory functions by orchestrating the functional outcome of phosphorylation by cAMP-dependent protein kinase ('PKA') and ERK. PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments.
756 citations
TL;DR: It is demonstrated that the muscle‐selective A‐kinase anchoring protein, mAKAP, maintains a cAMP signaling module, including PKA and the rolipram‐inhibited cAMP‐specific phosphodiesterase (PDE4D3) in heart tissues.
Abstract: Spatiotemporal regulation of protein kinase A (PKA) activity involves the manipulation of compartmentalized cAMP pools. Now we demonstrate that the muscle‐selective A‐kinase anchoring protein, mAKAP, maintains a cAMP signaling module, including PKA and the rolipram‐inhibited cAMP‐specific phosphodiesterase (PDE4D3) in heart tissues. Functional analyses indicate that tonic PDE4D3 activity reduces the activity of the anchored PKA holoenzyme, whereas kinase activation stimulates mAKAP‐associated phosphodiesterase activity. Disruption of PKA–mAKAP interaction prevents this enhancement of PDE4D3 activity, suggesting that the proximity of both enzymes in the mAKAP signaling complex forms a negative feedback loop to restore basal cAMP levels.
499 citations
TL;DR: It is shown that β-arrestins coordinate both processes by recruiting PDEs to activated β2-adrenergic receptors in the plasma membrane of mammalian cells by simultaneously slowing the rate of cAMP production through receptor desensitization and increasing the rates of its degradation at the membrane.
Abstract: Catecholamines signal through the β 2 -adrenergic receptor by promoting production of the second messenger adenosine 3′,5′-monophosphate (cAMP). The magnitude of this signal is restricted by desensitization of the receptors through their binding to β-arrestins and by cAMP degradation by phosphodiesterase (PDE) enzymes. We show that β-arrestins coordinate both processes by recruiting PDEs to activated β 2 -adrenergic receptors in the plasma membrane of mammalian cells. In doing so, the β-arrestins limit activation of membrane-associated cAMP-activated protein kinase by simultaneously slowing the rate of cAMP production through receptor desensitization and increasing the rate of its degradation at the membrane.
489 citations