Please use this identifier to cite or link to this item:
http://hdl.handle.net/1942/38051
Title: | Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types | Authors: | PAES, Dean Hermans, Sammy van den Hove, Daniel VANMIERLO, Tim Prickaerts, Jos Carlier, Aurelie |
Issue Date: | 2022 | Publisher: | CELL PRESS | Source: | BIOPHYSICAL JOURNAL, 121 (14) , p. 2693 -2711 | Abstract: | Cyclic adenosine monophosphate (cAMP) is a generic signaling molecule that, through precise control of its signaling dynamics, exerts distinct cellular effects. Consequently, aberrant cAMP signaling can have detrimental effects. Phos-phodiesterase 4 (PDE4) enzymes profoundly control cAMP signaling and comprise different isoform types wherein enzymatic activity is modulated by differential feedback mechanisms. Because these feedback dynamics are non-linear and occur coinci-dentally, their effects are difficult to examine experimentally but can be well simulated computationally. Through understanding the role of PDE4 isoform types in regulating cAMP signaling, PDE4-targeted therapeutic strategies can be better specified. Here, we established a computational model to study how feedback mechanisms on different PDE4 isoform types lead to dynamic, isoform-specific control of cAMP signaling. Ordinary differential equations describing cAMP dynamics were implemented in the VirtualCell environment. Simulations indicated that long PDE4 isoforms exert the most profound control on oscillatory cAMP signaling, as opposed to the PDE4-mediated control of single cAMP input pulses. Moreover, elevating cAMP levels or decreasing PDE4 levels revealed different effects on downstream signaling. Together these results underline that cAMP signaling is distinctly regulated by different PDE4 isoform types and that this isoform specificity should be considered in both computational and experimental follow-up studies to better define PDE4 enzymes as therapeutic targets in diseases in which cAMP signaling is aberrant. | Notes: | Carlier, A (corresponding author), Maastricht Univ, MERLN Inst Technol Inspired Regenerat Med, Maastricht, Netherlands. a.carlier@maastrichtuniversity.nl |
Document URI: | http://hdl.handle.net/1942/38051 | ISSN: | 0006-3495 | e-ISSN: | 1542-0086 | DOI: | 10.1016/j.bpj.2022.06.019 | ISI #: | 000837982600004 | Rights: | 2022 Biophysical Society. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2023 |
Appears in Collections: | Research publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Computational.pdf | Peer-reviewed author version | 997.81 kB | Adobe PDF | View/Open |
Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types.pdf Restricted Access | Published version | 2.75 MB | Adobe PDF | View/Open Request a copy |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.