Croft2013 - GPCR-RGS interaction that compartmentalizes RGS activity

Croft2013 - GPCR-RGS interaction that compartmentalizes RGS activity
Through modelling studies, the classic quaternary complex (ligand-GPCR-G-RGS) has been extended to include an additional layer of regulation through GPCR-RGS interactions, which facilitate the compartmentalization of RGS activity into the plasma membrane and non-plasma compartments.

This model is described in the article:
A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.

Croft W, Hill C, McCann E, Bond M, Esparza-Franco M, Bennett J, Rand D, Davey J, Ladds G.
J Biol Chem. 2013 Sep 20;288(38):27327-42.
Abstract:
G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways.

Author's comment on reproducing the plots:

To reproduce dose-response plots in the publication, the model is simulated with 12 different ligand concentrations (see parameter Ligand_conc).
For each ligand concentration, a single value corresponding to total amount of output must be obtained, by calculating the area under the curve of the trajectory of species z3, from time=0 to time=30.
These total output values are then used to build a dose-response plot (authors used GraphPad Prism).
Mutant strains are simulated with alternative parameter values or initial conditions specified in the Supplementary Material.

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