ArticlePloS one2010
The role of type 4 phosphodiesterases in generating microdomains of cAMP: large scale stochastic simulations.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 120 citations in OpenAlex.
- GPCR signaling via cAMP nanodomains.The Biochemical journal · 2025Review
- Quantitative Systems Pharmacology Development and Application in Neuroscience.Handbook of experimental pharmacology · 2025Review
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- A two-dimensional finite element model of intercellular cAMP signaling through gap junction channels.Journal of biomechanics · 2023Article
- Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types.Biophysical journal · 2022Article
- Article
- Influence of T-Bar on Calcium Concentration Impacting Release Probability.Frontiers in computational neuroscience · 2022Article
- STEPS 4.0: Fast and memory-efficient molecular simulations of neurons at the nanoscale.Frontiers in neuroinformatics · 2022Article
- HillTau: A fast, compact abstraction for model reduction in biochemical signaling networks.PLoS computational biology · 2021Article
- Mechanisms of cAMP compartmentation in cardiac myocytes: experimental and computational approaches to understanding.The Journal of physiology · 2021Review
- A three-dimensional finite element model of cAMP signals.Forces in mechanics · 2021Article
- Antidepressants Produce Persistent GMolecular pharmacology · 2021Article
- Cyclic adenosine monophosphate (cAMP) signaling in melanocyte pigmentation and melanomagenesis.Pigment cell & melanoma research · 2021Review
- Subcellular Organization of the cAMP Signaling Pathway.Pharmacological reviews · 2021Review
- Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator.PLoS computational biology · 2020Article
- Review
- 3D mesh processing using GAMer 2 to enable reaction-diffusion simulations in realistic cellular geometries.PLoS computational biology · 2020Article
- Applications and Challenges of Machine Learning to Enable Realistic Cellular Simulations.Frontiers in physics · 2020Article
- PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells.Frontiers in pharmacology · 2020Article
- A two-dimensional finite element model of cyclic adenosine monophosphate (cAMP) intracellular signaling.SN applied sciences · 2019Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 5 institutions in 3 countries.
Funding
Abstract
Cyclic AMP (cAMP) and its main effector Protein Kinase A (PKA) are critical for several aspects of neuronal function including synaptic plasticity. Specificity of synaptic plasticity requires that cAMP activates PKA in a highly localized manner despite the speed with which cAMP diffuses. Two mechanisms have been proposed to produce localized elevations in cAMP, known as microdomains: impeded diffusion, and high phosphodiesterase (PDE) activity. This paper investigates the mechanism of localized cAMP signaling using a computational model of the biochemical network in the HEK293 cell, which is a subset of pathways involved in PKA-dependent synaptic plasticity. This biochemical network includes cAMP production, PKA activation, and cAMP degradation by PDE activity. The model is implemented in NeuroRD: novel, computationally efficient, stochastic reaction-diffusion software, and is constrained by intracellular cAMP dynamics that were determined experimentally by real-time imaging using an Epac-based FRET sensor (H30). The model reproduces the high concentration cAMP microdomain in the submembrane region, distinct from the lower concentration of cAMP in the cytosol. Simulations further demonstrate that generation of the cAMP microdomain requires a pool of PDE4D anchored in the cytosol and also requires PKA-mediated phosphorylation of PDE4D which increases its activity. The microdomain does not require impeded diffusion of cAMP, confirming that barriers are not required for microdomains. The simulations reported here further demonstrate the utility of the new stochastic reaction-diffusion algorithm for exploring signaling pathways in spatially complex structures such as neurons.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.