Bush2016 - Extended Carrousel model of GPCR-RGS

Bush2016 - Extended Carrousel model of
GPCR-RGS

This model is described in the article:

Yeast GPCR signaling
reflects the fraction of occupied receptors, not the
number.

Bush A, Vasen G, Constantinou A,
Dunayevich P, Patop IL, Blaustein M, Colman-Lerner A.
Mol. Syst. Biol. 2016 Dec; 12(12):
898
Abstract:

According to receptor theory, the effect of a ligand depends
on the amount of agonist-receptor complex. Therefore, changes
in receptor abundance should have quantitative effects.
However, the response to pheromone in Saccharomyces cerevisiae
is robust (unaltered) to increases or reductions in the
abundance of the G-protein-coupled receptor (GPCR), Ste2,
responding instead to the fraction of occupied receptor. We
found experimentally that this robustness originates during
G-protein activation. We developed a complete mathematical
model of this step, which suggested the ability to compute
fractional occupancy depends on the physical interaction
between the inhibitory regulator of G-protein signaling (RGS),
Sst2, and the receptor. Accordingly, replacing Sst2 by the
heterologous hsRGS4, incapable of interacting with the
receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2
interaction restored robustness. Taken together with other
results of our work, we conclude that this GPCR pathway
computes fractional occupancy because ligand-bound GPCR-RGS
complexes stimulate signaling while unoccupied complexes
actively inhibit it. In eukaryotes, many RGSs bind to specific
GPCRs, suggesting these complexes with opposing activities also
detect fraction occupancy by a ratiometric measurement. Such
complexes operate as push-pull devices, which we have recently
described.

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