原创力文档the role of type 4 phosphodiesterases in generating microdomains of camp large scale stochastic simulations4型磷酸二酯酶的作用产生microdomains营地大规模随机模拟.pdfVIP
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the role of type 4 phosphodiesterases in generating microdomains of camp large scale stochastic simulations4型磷酸二酯酶的作用产生microdomains营地大规模随机模拟
The Role of Type 4 Phosphodiesterases in Generating
Microdomains of cAMP: Large Scale Stochastic
Simulations
1 2 3 4 1
Rodrigo F. Oliveira , Anna Terrin , Giulietta Di Benedetto , Robert C. Cannon , Wonryull Koh ,
1 2 1
MyungSook Kim , Manuela Zaccolo , Kim T. Blackwell *
1The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America, 2 Faculty of Biomedical and Life Sciences, University of
Glasgow, Glasgow, Scotland, United Kingdom, 3 Venetian Institute of Molecular Medicine, Padova, Veneto, Italy, 4 Textensor Limited, Edinburgh, Scotland, United
Kingdom
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 re
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