Anchoring proteins and phosphodiesterases: A stochastic reaction diffusion simulation of cAMP microdomains
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1
George Mason University, United States
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2
Krasnow Institute for Advanced Studies, United States
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3
Faculty of Biomedical & Life Sciences, United Kingdom
Cyclic AMP (cAMP) is an important second messenger molecule responsible for regulation of many aspects of cell function such as long term synaptic plasticity in neurons. Though cAMP diffuses throughout a cell relatively rapidly, specificity in cAMP activation of downstream targets is achieved by mechanisms which produce spatial gradients and microdomains of cAMP concentration. Recent experiments suggest that compartmentalized phosphodiesterases (PDE) act as localized 'sinks', producing gradients of cAMP.
To test the role of compartmentalized PDEs in producing spatial gradients, we develop a computational model of cAMP production, PKA activation and compartmentalized PDE activity using the Rapid, Approximate, Stochastic reaction-diffusion (RASrd) algorithm. In the model cell, adenylyl cyclase, PKA and PDE4B are anchored to the submembrane compartment, PKA and PDE4D are anchored in the cytosol, and cAMP freely diffuses. To precisely compare simulated results with FRET imaging data, we calculate the theoretical FRET signal from simulated concentrations of cAMP bound and free Epac or PKA, and include contamination terms due to overlap of emission and excitation spectra. The model reproduces the cAMP gradient (both free cAMP and the calculated FRET signal) between submembrane and cytosolic compartments. Simulations results with reduced PDE activity and different cAMP diffusion constants also show the dependence of the gradient on both PDE4D cytosoloic anchoring and cAMP diffusion suggesting that reduced cAMP diffusivity may also play a role in compartmentalization. Furthermore, our simulations demonstrate the utility of the new stochastic reaction-diffusion algorithm for exploring signaling pathways in spatially complex structures such as neurons.
Conference:
Neuroinformatics 2008, Stockholm, Sweden, 7 Sep - 9 Sep, 2008.
Presentation Type:
Poster Presentation
Topic:
Computational Neuroscience
Citation:
Oliveira
RF,
Kim
M,
Blackwell
KT and
Zaccolo
M
(2008). Anchoring proteins and phosphodiesterases: A stochastic reaction diffusion simulation of cAMP microdomains.
Front. Neuroinform.
Conference Abstract:
Neuroinformatics 2008.
doi: 10.3389/conf.neuro.11.2008.01.048
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Received:
28 Jul 2008;
Published Online:
28 Jul 2008.
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Correspondence:
Rodrigo F Oliveira, George Mason University, Fairfax, United States, roliveir@gmu.edu