Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types

Paes, Dean; Hermans, Sammy; Hove, Daniël van den; Vanmierlo, Tim; Prickaerts, Jos; Carlier, Aurélie

doi:10.1016/j.bpj.2022.06.019

Cited by 5 publications

(2 citation statements)

References 96 publications

(130 reference statements)

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“… 39 PDE4 isoforms are essential spatiotemporal regulators of cAMP signalling due to their distinct intracellular distribution patterns, dynamic activity regulation, and isoform-specific regulation. 40 PDE4 isoform selective inhibitors do not yet exist. Therefore, it will be important to create novel isoform specific PDE4 inhibitors also because this approach may help to reduce side effects.…”

Section: Inhibition Of Recruitment and Activation Of The Inflammatory...mentioning

confidence: 99%

Novel Anti-Inflammatory Approaches to COPD

Cazzola¹,

Hanania²,

Page³

et al. 2023

COPD

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Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4 + and CD8 + T lymphocytes are key players in this process, although the extent of their participation varies according to the patient's endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD.

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Section: Inhibition Of Recruitment and Activation Of The Inflammatory...mentioning

confidence: 99%

Novel Anti-Inflammatory Approaches to COPD

Cazzola¹,

Hanania²,

Page³

et al. 2023

COPD

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“…The PDE sinks of cAMP can also be membrane-bound or soluble, and individual cells might have different isoforms of PDEs that are active at different cAMP concentrations (i.e. have different Michaelis constants 𝐾𝐾 𝑚𝑚 ) (22,(36)(37)(38). Membrane-bound enzymes (AC or PDE) have a higher effective concentration in regions of higher surface-to-volume ratio, even if homogeneously distributed and homogeneously activated throughout the cell membrane.…”

Section: Camp Is Geometrically Compartmentalized In Membrane Asperiti...mentioning

confidence: 99%

All-optical mapping of cAMP transport reveals rules of sub-cellular localization

Xiang

Park

Koren

et al. 2023

Preprint

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Cyclic adenosine monophosphate (cAMP) is a second messenger that mediates diverse intracellular signals. Studies of cAMP transport in cells have produced wildly different results, from reports of nearly free diffusion to reports that cAMP remains localized in nanometer-scale domains. We developed an all-optical toolkit, termed cAMP-SITES, to locally perturb and map cAMP transport. In MDCK cells and in cultured neurons, cAMP had a diffusion coefficient of ~120 μm2/s, similar to the diffusion coefficients of other small molecules in cytoplasm. In neuronal dendrites, a balance between diffusion and degradation led to cAMP domains with a length scale of ~30 μm. Geometrical confinement by membranes led to subcellular variations in cAMP concentration, but we found no evidence of nanoscale domains or of distinct membrane-local and cytoplasmic pools. We introduce theoretical relations between cell geometry and small-molecule reaction-diffusion dynamics and transport to explain our observations.

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Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement

Wei

Shen

et al. 2023

Bioorganic Chemistry

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Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types

Cited by 5 publications

References 96 publications

Novel Anti-Inflammatory Approaches to COPD

Novel Anti-Inflammatory Approaches to COPD

All-optical mapping of cAMP transport reveals rules of sub-cellular localization

Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement

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