Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action

Francis, Sharron H.; Houslay, Miles D.; Conti, Marco

doi:10.1007/978-3-642-17969-3_2

Cited by 52 publications

(54 citation statements)

References 185 publications

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“…The AC activity is also regulated by protein phosphorylation (17). The intracellular concentration of cAMP is further controlled by PDEs, which degrade cAMP to the inactive 5′-AMP (22).…”

Section: Discussionmentioning

confidence: 99%

Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production

Pulliainen

Pieles

Brand

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Subversion of host organism cAMP signaling is an efficient and widespread mechanism of microbial pathogenesis. Bartonella effector protein A (BepA) of vasculotumorigenic Bartonella henselae protects the infected human endothelial cells against apoptotic stimuli by elevation of cellular cAMP levels by an as yet unknown mechanism. Here, adenylyl cyclase (AC) and the α-subunit of the AC-stimulating G protein (Gαs) were identified as potential cellular target proteins for BepA by gel-free proteomics. Results of the proteomics screen were evaluated for physical and functional interaction by: (i) a heterologous in vivo coexpression system, where human AC activity was reconstituted under the regulation of Gαs and BepA in Escherichia coli; (ii) in vitro AC assays with membrane-anchored fulllength human AC and recombinant BepA and Gαs; (iii) surface plasmon resonance experiments; and (iv) an in vivo fluorescence bimolecular complementation-analysis. The data demonstrate that BepA directly binds host cell AC to potentiate the Gαs-dependent cAMP production. As opposed to the known microbial mechanisms, such as ADP ribosylation of G protein α-subunits by cholera and pertussis toxins, the fundamentally different BepA-mediated elevation of host cell cAMP concentration appears subtle and is dependent on the stimulus of a G protein-coupled receptor-released Gαs. We propose that this mechanism contributes to the persistence of Bartonella henselae in the chronically infected vascular endothelium.bacterial infection | apoptosis | tumorigenesis | type IV secretion

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“…The AC activity is also regulated by protein phosphorylation (17). The intracellular concentration of cAMP is further controlled by PDEs, which degrade cAMP to the inactive 5′-AMP (22).…”

Section: Discussionmentioning

confidence: 99%

Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production

Pulliainen

Pieles

Brand

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…However, this treatment is not frequently recommended because of its side effects and nonselective nature (39). Drugs specifically targeting phosphodiesterase, such as PDE4 inhibitor (roflumilast), have been shown to improve lung function in patients with COPD.…”

Section: Anti-inflammatory Therapeutic Strategies-targeting Immune Homentioning

confidence: 99%

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

Zuo

Sergakis

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

216

139

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Cigarette smoking (CS) can impact the immune system and induce pulmonary disorders such as chronic obstructive pulmonary disease (COPD), which is currently the fourth leading cause of chronic morbidity and mortality worldwide. Accordingly, the most significant risk factor associated with COPD is exposure to cigarette smoke. The purpose of the present study is to provide an updated overview of the literature regarding the effect of CS on the immune system and lungs, the mechanism of CS-induced COPD and oxidative stress, as well as the available and potential treatment options for CS-induced COPD. An extensive literature search was conducted on the PubMed/Medline databases to review current COPD treatment research, available in the English language, dating from 1976 to 2014. Studies have investigated the mechanism by which CS elicits detrimental effects on the immune system and pulmonary function through the use of human and animal subjects. A strong relationship among continued tobacco use, oxidative stress, and exacerbation of COPD symptoms is frequently observed in COPD subjects. In addition, therapeutic approaches emphasizing smoking cessation have been developed, incorporating counseling and nicotine replacement therapy. However, the inability to reverse COPD progression establishes the need for improved preventative and therapeutic strategies, such as a combination of intensive smoking cessation treatment and pharmaceutical therapy, focusing on immune homeostasis and redox balance. CS initiates a complex interplay between oxidative stress and the immune response in COPD. Therefore, multiple approaches such as smoking cessation, counseling, and pharmaceutical therapies targeting inflammation and oxidative stress are recommended for COPD treatment.

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“…Responsibility for degrading these 3′,5′-cyclic nucleotides, and thereby limiting the duration and amplitude of the signals that they convey, falls to enzymes of the intracellular phosphodiesterase family (PDEs). The significance of these enzymes in cellular control makes them important targets of medicinal discovery, and maximizing our understanding of their respective structures and activities is an urgent priority (6).…”

mentioning

confidence: 99%

Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4

Cedervall

Aulabaugh

Geoghegan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-links cysteines engineered into UCR2 and the catalytic domain. Biochemical and mass spectrometric analyses showed that the UCR2-catalytic domain interaction occurs in trans, and established that this interaction regulates the catalytic activity of PDE4. By elucidating the key structural determinants of dimerization, we show that only long forms of PDE4 can be regulated by this mechanism. The results also provide a structural basis for the long-standing observation of high-and low-affinity binding sites for the prototypic inhibitor rolipram.T he diverse, pivotal roles of cAMP and cGMP (1) in mammalian intracellular signaling include acting as "second messengers" of signals delivered through G protein-coupled receptors (2), regulating the opening and closing of ligand-gated ion-channels (3), activating guanine-nucleotide exchange factors (4), and activating kinase signaling cascades (5). Responsibility for degrading these 3′,5′-cyclic nucleotides, and thereby limiting the duration and amplitude of the signals that they convey, falls to enzymes of the intracellular phosphodiesterase family (PDEs). The significance of these enzymes in cellular control makes them important targets of medicinal discovery, and maximizing our understanding of their respective structures and activities is an urgent priority (6).Mammalian PDEs are encoded by 21 genes and divided into 11 families (PDE1 to -11) defined by their amino acid sequences, with supporting distinctions based on pharmacologic and kinetic properties. Among the most intriguing of these families is PDE4, the four members (PDE4A to -D) of which have high selectivity for cAMP over cGMP as substrate and are characteristically sensitive to inhibition by rolipram. PDE4 inhibition has been pursued as a therapeutic target for over 30 y, since the first discovery of the potential efficacy of rolipram in treating clinical depression (7). Two different PDE4 inhibitors, roflumilast (Daxas) and apremilast (Otezla), are Food and Drug Administration-approved therapies for exacerbations of chronic obstructive pulmonary disease and psoriatic arthritis, respectively, and several others are in clinical trials for a variety of indications.Because of alternative promoters/start sites and variable mRNA splicing, transcription from the four PDE4 genes results in the expression of more than 25 different isoforms of PDE4. Each isoform has a unique N...

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Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action

Cited by 52 publications

References 185 publications

Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production

Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4

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