Lipid raft-mediated regulation of G-protein coupled receptor signaling by ligands which influence receptor dimerization: a computational study.
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.
Fallahi-Sichani
Mohammad
M
Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
Linderman
Jennifer J
JJ
D019281:Dimerization; D008024:Ligands; D021962:Membrane Microdomains / Q000502:physiology*; D009010:Monte Carlo Method; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D008024:Ligands; D043562:Receptors, G-Protein-Coupled