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Review
. 2009 Feb 27;284(9):5445-9.
doi: 10.1074/jbc.R800058200. Epub 2008 Oct 20.

Models of Spatially Restricted Biochemical Reaction Systems

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Free PMC article
Review

Models of Spatially Restricted Biochemical Reaction Systems

Susana R Neves et al. J Biol Chem. .
Free PMC article

Abstract

Many reactions within the cell occur only in specific intracellular regions. Such local reaction networks give rise to microdomains of activated signaling components. The dynamics of microdomains can be visualized by live cell imaging. Computational models using partial differential equations provide mechanistic insights into the interacting factors that control microdomain dynamics. The mathematical models show that, for membrane-initiated signaling, the ratio of the surface area of the plasma membrane to the volume of the cytoplasm, the topology of the signaling network, the negative regulators, and kinetic properties of key components together define microdomain dynamics. Thus, patterns of locally restricted signaling reaction systems can be considered an emergent property of the cell.

Figures

FIGURE 1.
FIGURE 1.
cAMP microdomains in cardiac myocytes. A, experimental demonstration of the cAMP microdomain in a study by Zaccolo and Pozzan (9) reprinted with permission from AAAS. The fluorescence resonance energy transfer ratio images are color-coded, with green signifying basal concentrations of cAMP and yellow to red signifying high concentrations of cAMP. Scale bar = 10 μm. The white arrow in the enlarged image points to a cAMP microdomain (∼1 μm). B, simulation in Virtual Cell of receptor-triggered cAMP increases using the cell shape traced from the myocyte image in A. The black arrow shows the corresponding cAMP microdomain in same region as in A. C, schematic diagram of factors controlling cAMP microdomains in myocytes: plasma membrane (PM) localization of adenylyl cyclase (AC), separation of production and degradation (phosphodiesterase (PDE)) activities for cAMP, and diffusion hindrance by intracellular organelles such as the sarcoplasmic reticulum (SR, depicted as the black double dashed line). D, microdomain characteristics are defined by the highest concentration point within the microdomain and the resulting gradient that extends to the periphery and defines the microdomain boundary. These are represented as a function of distance from the site of production. Arbitrary numbers are used for illustrative purposes.
FIGURE 2.
FIGURE 2.
Multiple factors regulate microdomain dynamics and the flow of spatial information. A, schematic of the spatially specified network topology used in the simulations. B–D, simulations of microdomains of signaling components in a dendritic arbor of a neuron. In all cases the signal originates at the plasma membrane. B, S/V ratios regulate microdomains. Regions of high S/V ratios show increased levels of activated PKA (PKA*) compared with regions with low S/V ratios. C, cytoplasmic negative regulators control microdomain characteristics. Upper panel, uniform activation of PKA when the phosphodiesterase is inhibited; lower panel (same image as in A), PKA microdomains when phosphodiesterase is active. D, network topology and kinetic parameters control the transfer of microdomain characteristics (i.e. spatial information) from upstream to downstream components. These simulations show that kinetic parameters are crucial factors in determining the transfer of microdomain characteristics. In the model, PKA has a high Kcat for b-Raf, which leads to extensive activation of b-Raf and loss of microdomains. In contrast, PKA has a low Kcat for PTPSL, resulting in microdomains of phosphorylated PTPSL (PTPSLi) that are similar to those of PKA. The regulation of PTP by PKA* leads to two populations of phosphatase activity, PKA*-inhibited activity (PTPSLi) and the active non-phosphorylated enzyme (PTPSL*). Areas with a high concentration of PKA* have low PTP activity and consequently high phospho-MAPK. Areas with a low concentration of PKA* have high PTP activity and low phospho-MAPK. This spatial and activity heterogeneity of PTPSL results in recapitulating the PKA* microdomains as MAPK* microdomains.

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