G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, and are the targets of a substantial fraction of all prescribed ad abused drugs. It is widely accepted that members of the largest GPCR family (class A receptors) self-assemble as dimers or higher-order oligomers, and GPCR dimers have been proposed as potential targets for novel therapeutic drugs. However, functional consequences of dimerization have been described for only a few receptors, and ligands that bind specifically to dimers have not been found. The main goal of this project is to test the hypothesis that most interactions between classes A protomers are both transient and structurally nonspecific. If this is the case, it would explain why dimerization is rarely leads to overt functional changes or unique binding sites. The objective of the proposed project is to determine the physical stability of interactions between a large sample of class A receptors and transmembrane control proteins using fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), time-resolved fluorescence resonance energy transfer (TR-FRET), and an affinity-based on-cell corecruitment assay. Inclusion of a large sample of non-GPCR control proteins will allow us to determine if physical interactions between classes A protomers are special, or are typical of interactions between polytopic transmembrane proteins in general. These experiments will better define the quaternary structure of the largest subfamily of GPCRs, and may force a revision of the standard model that currently motivates the search for dimer-selective drugs.

Public Health Relevance

G protein-coupled receptors are the targets of more prescribed drugs than any other class of receptor. The realization that GPCRs can assemble as dimers or higher-order oligomers suggests the possibility that these complexes might have unique pharmacological properties, thus greatly expanding the number of potential therapeutic targets. However, relatively few dimer-specific functions or selective ligands have been found. This project seeks to explain why dimerization rarely changes receptor function. If successful the project will revise the current model of GPCR quaternary structure, and could provide a means to identify bona fide receptor dimers as prospective drug targets

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM078319-05A1
Application #
8718138
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
Project Start
2007-09-25
Project End
2017-12-31
Budget Start
2014-04-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$247,500
Indirect Cost
$82,500
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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