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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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Predicted variation in the enrichment ratio with kmono and kdimer as a function of the total area (as a percentage of the cell membrane area) and diameter of lipid rafts.Results are shown for receptor densities of (A) 18% and (B) 1.8% of the cell surface area. For each pair of raft diameter and raft coverage, kmono and kdimer are varied from 104 to 107 s−1 so as to include monomer, dimer and oligomer regimes. Diffusion coefficients in lipid raft and non-raft regions are 10−11 cm2/s and 10−10 cm2/s respectively.
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pone-0006604-g004: Predicted variation in the enrichment ratio with kmono and kdimer as a function of the total area (as a percentage of the cell membrane area) and diameter of lipid rafts.Results are shown for receptor densities of (A) 18% and (B) 1.8% of the cell surface area. For each pair of raft diameter and raft coverage, kmono and kdimer are varied from 104 to 107 s−1 so as to include monomer, dimer and oligomer regimes. Diffusion coefficients in lipid raft and non-raft regions are 10−11 cm2/s and 10−10 cm2/s respectively.

Mentions: Cell-specific parameters such as raft diameter, raft area, and receptor number may also influence receptor organization. We next examined the effect of the size of a single raft and total lipid raft area on the membrane organization of receptors. Figure 4 indicates simulation results for the range of dimerization-mediated enrichment of receptors in lipid rafts for two distinct numbers of receptors on the cell membrane. Enrichment of receptors in lipid rafts depends weakly on raft diameter. However, total raft area significantly influences the range of dimerization-mediated receptor enrichment in lipid rafts. Figure 4 shows that increasing the area of cell membrane covered by lipid rafts limits the range of variation of enrichment ratio with dimerization and monomerization rate constants. Dependency of receptor enrichment on lipid raft characteristics has a clear biological relevance. Partitioning of receptors with small non-caveolae rafts with a small cell surface coverage and their localization with larger caveolae that occupy 4–35% of the cell membrane area are expected to have different consequences [51].


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)

Predicted variation in the enrichment ratio with kmono and kdimer as a function of the total area (as a percentage of the cell membrane area) and diameter of lipid rafts.Results are shown for receptor densities of (A) 18% and (B) 1.8% of the cell surface area. For each pair of raft diameter and raft coverage, kmono and kdimer are varied from 104 to 107 s−1 so as to include monomer, dimer and oligomer regimes. Diffusion coefficients in lipid raft and non-raft regions are 10−11 cm2/s and 10−10 cm2/s respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006604-g004: Predicted variation in the enrichment ratio with kmono and kdimer as a function of the total area (as a percentage of the cell membrane area) and diameter of lipid rafts.Results are shown for receptor densities of (A) 18% and (B) 1.8% of the cell surface area. For each pair of raft diameter and raft coverage, kmono and kdimer are varied from 104 to 107 s−1 so as to include monomer, dimer and oligomer regimes. Diffusion coefficients in lipid raft and non-raft regions are 10−11 cm2/s and 10−10 cm2/s respectively.
Mentions: Cell-specific parameters such as raft diameter, raft area, and receptor number may also influence receptor organization. We next examined the effect of the size of a single raft and total lipid raft area on the membrane organization of receptors. Figure 4 indicates simulation results for the range of dimerization-mediated enrichment of receptors in lipid rafts for two distinct numbers of receptors on the cell membrane. Enrichment of receptors in lipid rafts depends weakly on raft diameter. However, total raft area significantly influences the range of dimerization-mediated receptor enrichment in lipid rafts. Figure 4 shows that increasing the area of cell membrane covered by lipid rafts limits the range of variation of enrichment ratio with dimerization and monomerization rate constants. Dependency of receptor enrichment on lipid raft characteristics has a clear biological relevance. Partitioning of receptors with small non-caveolae rafts with a small cell surface coverage and their localization with larger caveolae that occupy 4–35% of the cell membrane area are expected to have different consequences [51].

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