title: A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.
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.
authors.affiliation: Division of Biomedical Cell Biology, Warwick Medical School.
authors.forename: Wayne
authors.initials: W
authors.lastname: Croft
authors.affiliation: School of Life Sciences.
authors.forename: Claire
authors.initials: C
authors.lastname: Hill
authors.affiliation: Division of Biomedical Cell Biology, Warwick Medical School.
authors.forename: Eilish
authors.initials: E
authors.lastname: McCann
authors.affiliation: Division of Biomedical Cell Biology, Warwick Medical School.
authors.forename: Michael
authors.initials: M
authors.lastname: Bond
authors.affiliation: Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Manuel
authors.initials: M
authors.lastname: Esparza-Franco
authors.affiliation: Division of Biomedical Cell Biology, Warwick Medical School.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Rand
authors.affiliation: Division of Biomedical Cell Biology, Warwick Medical School.
authors.forename: John
authors.initials: J
authors.lastname: Davey
authors.affiliation: Division of Biomedical Cell Biology, Warwick Medical School. Electronic address: Graham.Ladds@warwick.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Ladds
mesh_terms: D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020710:RGS Proteins; D043562:Receptors, G-Protein-Coupled; C489854:Rgs1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins
keywords: Cell Compartmentation; Cell Signaling; G Protein-coupled Receptors (GPCR); GTPase; Kinetics; Mathematical Modeling; RGS Proteins; Signal Transduction
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