AI Article Synopsis
- cAMP is a crucial signaling molecule in cells, and its regulation can significantly affect cellular functions; improper signaling can lead to negative outcomes.
- Phosphodiesterase 4 (PDE4) enzymes play a critical role in controlling cAMP levels, with various isoforms modulating signaling in complex, non-linear ways that are challenging to study directly but can be modeled effectively using computational simulations.
- A computational model demonstrated that different PDE4 isoforms distinctly influence cAMP dynamics, highlighting that long PDE4 isoforms have the greatest impact on oscillatory signaling and suggesting that further research should focus on isoform-specific regulation for potential therapeutic advancements.
Article 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. Phosphodiesterase 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 coincidentally, 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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9382341 | PMC |
| http://dx.doi.org/10.1016/j.bpj.2022.06.019 | DOI Listing |
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