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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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Simulation results for proposed experimental protocols for (A) amplification of G-protein signaling in the presence of lipid rafts with 2% coverage, and (B) attenuation of G-protein signaling in the presence of lipid rafts with 30% coverage.Baseline experiments are performed using khyd = 10 s−1, Rtot = 50,000 #/cell and [L] = 0.1Kd. The effects of a change in a single parameter are shown by experiments I-III (experiment I∶khyd = 1 s−1, experiment II∶Rtot = 250,000 #/cell and experiment III∶[L] = Kd). The effect of a simultaneous change in all three parameters is shown by experiment IV (khyd = 1 s−1, Rtot = 250,000 #/cell and [L] = Kd). The greatest enrichment ratio for ligand-bound receptors predicted by MC model was used in each simulation. Other parameter values are as listed in Table 1.
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pone-0006604-g008: Simulation results for proposed experimental protocols for (A) amplification of G-protein signaling in the presence of lipid rafts with 2% coverage, and (B) attenuation of G-protein signaling in the presence of lipid rafts with 30% coverage.Baseline experiments are performed using khyd = 10 s−1, Rtot = 50,000 #/cell and [L] = 0.1Kd. The effects of a change in a single parameter are shown by experiments I-III (experiment I∶khyd = 1 s−1, experiment II∶Rtot = 250,000 #/cell and experiment III∶[L] = Kd). The effect of a simultaneous change in all three parameters is shown by experiment IV (khyd = 1 s−1, Rtot = 250,000 #/cell and [L] = Kd). The greatest enrichment ratio for ligand-bound receptors predicted by MC model was used in each simulation. Other parameter values are as listed in Table 1.

Mentions: Ranges of parameters shown for the first 15 parameters (all independent) are used for sensitivity analysis. Values in parentheses are used to generate model results shown in Figures 6–8.


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)

Simulation results for proposed experimental protocols for (A) amplification of G-protein signaling in the presence of lipid rafts with 2% coverage, and (B) attenuation of G-protein signaling in the presence of lipid rafts with 30% coverage.Baseline experiments are performed using khyd = 10 s−1, Rtot = 50,000 #/cell and [L] = 0.1Kd. The effects of a change in a single parameter are shown by experiments I-III (experiment I∶khyd = 1 s−1, experiment II∶Rtot = 250,000 #/cell and experiment III∶[L] = Kd). The effect of a simultaneous change in all three parameters is shown by experiment IV (khyd = 1 s−1, Rtot = 250,000 #/cell and [L] = Kd). The greatest enrichment ratio for ligand-bound receptors predicted by MC model was used in each simulation. Other parameter values are as listed in Table 1.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006604-g008: Simulation results for proposed experimental protocols for (A) amplification of G-protein signaling in the presence of lipid rafts with 2% coverage, and (B) attenuation of G-protein signaling in the presence of lipid rafts with 30% coverage.Baseline experiments are performed using khyd = 10 s−1, Rtot = 50,000 #/cell and [L] = 0.1Kd. The effects of a change in a single parameter are shown by experiments I-III (experiment I∶khyd = 1 s−1, experiment II∶Rtot = 250,000 #/cell and experiment III∶[L] = Kd). The effect of a simultaneous change in all three parameters is shown by experiment IV (khyd = 1 s−1, Rtot = 250,000 #/cell and [L] = Kd). The greatest enrichment ratio for ligand-bound receptors predicted by MC model was used in each simulation. Other parameter values are as listed in Table 1.
Mentions: Ranges of parameters shown for the first 15 parameters (all independent) are used for sensitivity analysis. Values in parentheses are used to generate model results shown in Figures 6–8.

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