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Lipid raft-mediated regulation of G-protein coupled receptor signaling by ligands which influence receptor dimerization: a computational study.

Fallahi-Sichani M, Linderman JJ - PLoS ONE (2009)

Bottom Line: Using a combination of stochastic (Monte Carlo) and deterministic modeling, we propose a novel mechanism for lipid raft partitioning of GPCRs based on reversible dimerization of receptors and then demonstrate that such localization can affect GPCR signaling.Modeling results are consistent with a variety of experimental data indicating that lipid rafts have a role in amplification or attenuation of G-protein signaling.Thus our work suggests a new mechanism by which dimerization-inducing or inhibiting characteristics of ligands can influence GPCR signaling by controlling receptor organization on the cell membrane.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.

ABSTRACT
G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors; they activate heterotrimeric G-proteins in response to ligand stimulation. Although many GPCRs have been shown to form homo- and/or heterodimers on the cell membrane, the purpose of this dimerization is not known. Recent research has shown that receptor dimerization may have a role in organization of receptors on the cell surface. In addition, microdomains on the cell membrane termed lipid rafts have been shown to play a role in GPCR localization. Using a combination of stochastic (Monte Carlo) and deterministic modeling, we propose a novel mechanism for lipid raft partitioning of GPCRs based on reversible dimerization of receptors and then demonstrate that such localization can affect GPCR signaling. Modeling results are consistent with a variety of experimental data indicating that lipid rafts have a role in amplification or attenuation of G-protein signaling. Thus our work suggests a new mechanism by which dimerization-inducing or inhibiting characteristics of ligands can influence GPCR signaling by controlling receptor organization on the cell membrane.

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Schematic showing the relationship between the Monte Carlo (MC) model of receptor dimerization and localization and the ordinary differential equation (ODE) model of G-protein signaling.Input parameters are shown by arrows pointing toward the models. Model outputs are shown by arrows pointing away from the models.
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pone-0006604-g001: Schematic showing the relationship between the Monte Carlo (MC) model of receptor dimerization and localization and the ordinary differential equation (ODE) model of G-protein signaling.Input parameters are shown by arrows pointing toward the models. Model outputs are shown by arrows pointing away from the models.

Mentions: To describe GPCR organization on the cell membrane due to dimerization and lipid raft partitioning and the effect of that organization on GPCR signaling, two separate models were used (Figure 1). First, a kinetic Monte Carlo (MC) model was developed to determine the effect of a ligand-induced change in the dimerization status of receptors on localization within low-diffusivity microdomains (lipid rafts) on the cell surface and to estimate the time-scale and level of receptor clustering and declustering. An MC framework allows examination of the roles of stochastic effects and partner switching in receptor organization and quantification of non-homogeneous receptor distributions in membrane microdomains. Second, an ordinary differential equation (ODE) model based on the collision coupling model [26], [27] was developed for studying the effect of receptor localization within lipid rafts on downstream signaling events. Linking this simple model to the MC model allows us to study and analyze G-protein activation while incorporating the effects of receptor organization; continuing to use the MC method for the activation part of the problem adds substantial computational time and complicates the sensitivity analysis without significant benefit. MC and ODE models and their inputs and outputs are linked as depicted in Figure 1.


Lipid raft-mediated regulation of G-protein coupled receptor signaling by ligands which influence receptor dimerization: a computational study.

Fallahi-Sichani M, Linderman JJ - PLoS ONE (2009)

Schematic showing the relationship between the Monte Carlo (MC) model of receptor dimerization and localization and the ordinary differential equation (ODE) model of G-protein signaling.Input parameters are shown by arrows pointing toward the models. Model outputs are shown by arrows pointing away from the models.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2719103&req=5

pone-0006604-g001: Schematic showing the relationship between the Monte Carlo (MC) model of receptor dimerization and localization and the ordinary differential equation (ODE) model of G-protein signaling.Input parameters are shown by arrows pointing toward the models. Model outputs are shown by arrows pointing away from the models.
Mentions: To describe GPCR organization on the cell membrane due to dimerization and lipid raft partitioning and the effect of that organization on GPCR signaling, two separate models were used (Figure 1). First, a kinetic Monte Carlo (MC) model was developed to determine the effect of a ligand-induced change in the dimerization status of receptors on localization within low-diffusivity microdomains (lipid rafts) on the cell surface and to estimate the time-scale and level of receptor clustering and declustering. An MC framework allows examination of the roles of stochastic effects and partner switching in receptor organization and quantification of non-homogeneous receptor distributions in membrane microdomains. Second, an ordinary differential equation (ODE) model based on the collision coupling model [26], [27] was developed for studying the effect of receptor localization within lipid rafts on downstream signaling events. Linking this simple model to the MC model allows us to study and analyze G-protein activation while incorporating the effects of receptor organization; continuing to use the MC method for the activation part of the problem adds substantial computational time and complicates the sensitivity analysis without significant benefit. MC and ODE models and their inputs and outputs are linked as depicted in Figure 1.

Bottom Line: Using a combination of stochastic (Monte Carlo) and deterministic modeling, we propose a novel mechanism for lipid raft partitioning of GPCRs based on reversible dimerization of receptors and then demonstrate that such localization can affect GPCR signaling.Modeling results are consistent with a variety of experimental data indicating that lipid rafts have a role in amplification or attenuation of G-protein signaling.Thus our work suggests a new mechanism by which dimerization-inducing or inhibiting characteristics of ligands can influence GPCR signaling by controlling receptor organization on the cell membrane.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.

ABSTRACT
G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors; they activate heterotrimeric G-proteins in response to ligand stimulation. Although many GPCRs have been shown to form homo- and/or heterodimers on the cell membrane, the purpose of this dimerization is not known. Recent research has shown that receptor dimerization may have a role in organization of receptors on the cell surface. In addition, microdomains on the cell membrane termed lipid rafts have been shown to play a role in GPCR localization. Using a combination of stochastic (Monte Carlo) and deterministic modeling, we propose a novel mechanism for lipid raft partitioning of GPCRs based on reversible dimerization of receptors and then demonstrate that such localization can affect GPCR signaling. Modeling results are consistent with a variety of experimental data indicating that lipid rafts have a role in amplification or attenuation of G-protein signaling. Thus our work suggests a new mechanism by which dimerization-inducing or inhibiting characteristics of ligands can influence GPCR signaling by controlling receptor organization on the cell membrane.

Show MeSH