Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling

Conti, Marco; Beavo, Joseph A.

doi:10.1146/annurev.biochem.76.060305.150444

Cited by 1,054 publications

(1,020 citation statements)

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“…PDEs are crucial for negatively regulating cAMP levels and thus for the control of the individual local cAMP signalling events. At least five PDE families (PDE1-4 and 8) are expressed in the heart and can rapidly hydrolyse cAMP to AMP, thereby creating multiple contiguous cAMP microdomains 1,[9][10][11][12] . This enables the specificity of each cAMP response associated with local pools of PKA responsible for phosphorylation of particular downstream effectors.…”

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confidence: 99%

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

et al. 2015

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3 0 ,5 0 -cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger that regulates physiological functions by acting in distinct subcellular microdomains. Although several targeted cAMP biosensors are developed and used in single cells, it is unclear whether such biosensors can be successfully applied in vivo, especially in the context of disease. Here, we describe a transgenic mouse model expressing a targeted cAMP sensor and analyse microdomain-specific second messenger dynamics in the vicinity of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). We demonstrate the biocompatibility of this targeted sensor and its potential for real-time monitoring of compartmentalized cAMP signalling in adult cardiomyocytes isolated from a healthy mouse heart and from an in vivo cardiac disease model. In particular, we uncover the existence of a phosphodiesterase-dependent receptor-microdomain communication, which is affected in hypertrophy, resulting in reduced b-adrenergic receptor-cAMP signalling to SERCA.

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confidence: 99%

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

et al. 2015

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“…Phosphodiesterase 4 (PDE4) is a cAMP-specific PDE and the predominant PDE in inflammatory cells (21,22). Inhibition of PDE4 elevates intracellular cAMP levels, which, in turn, downregulates the inflammatory response by modulating the expression of TNF␣, interleukin-23 (IL-23), IL-12, and other inflammatory cytokines (21)(22)(23)(24). Elevation of cAMP increases the suppression of antiinflammatory cytokines such as IL-10.…”

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confidence: 99%

Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter, randomized, double‐blind, placebo‐controlled study

Schett¹,

Wollenhaupt²,

Papp³

et al. 2012

Arthritis & Rheumatism

186

100

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Objective. To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA).Methods. This phase II, multicenter, randomized, double-blind, placebo-controlled study included the following: a 12-week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12-week treatment-extension phase, with patients in the placebo group re-randomized to receive apremilast; and a 4-week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms.Results. Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P ‫؍‬ 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment-extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re-randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatmentextension phase (68.3%) reported >1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported.Conclusion. Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that is present in up to 30% of individuals ClinicalTrials.gov identifier: NCT00456092. This is protocol PSA-001 from the Celgene Corporation, Summit, NJ.

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“…The PDE superfamily consists of 11 different subfamilies (see Table 1) distinguished by their unique regulation, enzymatic characteristics, structure and pharmacological inhibitory profiles, as well as by their tissue, cellular and subcellular expression [68]. Each subfamily encompasses 1 to 4 distinct genes and each gene encodes multiple protein products generated by alternative splicing and/or the use of multiple promoters, resulting in more than 50 different PDE proteins identified in mammalian cells.…”

Section: Compartments Of Cyclic Nucleotide Signalingmentioning

confidence: 99%

“…This multiplicity of PDE proteins may allow specific intracellular localization of PDEs in the vicinity of various protein effectors inducing compartmentation and fine-tuning of cAMP and cGMP signals [69,70]. So far, all the phosphodiesterases identified consist of a modular architecture, with a highly conserved catalytic core located in the C-terminal part of the protein and distinct regulatory domains located in the N-terminal portion [68].…”

Section: Compartments Of Cyclic Nucleotide Signalingmentioning

confidence: 99%

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

Oliveira

Smolenski

2009

Biochemical Pharmacology

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Publication information Biochemical Pharmacology, 77 (4): 723-733Publisher Elsevier Item record/more information http://hdl.handle.net/10197/6007 Publisher's statementThis is the author's version of a work that was accepted for publication in Biochemical Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochemical Pharmacology (VOL 77, ISSUE 4, (2009)

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Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling

Cited by 1,054 publications

References 184 publications

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter, randomized, double‐blind, placebo‐controlled study

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

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