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

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Dunsmore, Sarah
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Georgia Regents University
Schools of Medicine
United States
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Lambert, Nevin A; Javitch, Jonathan A (2014) CrossTalk opposing view: Weighing the evidence for class A GPCR dimers, the jury is still out. J Physiol 592:2443-5
Promsote, Wanwisa; Veeranan-Karmegam, Rajalakshmi; Ananth, Sudha et al. (2014) L-2-oxothiazolidine-4-carboxylic acid attenuates oxidative stress and inflammation in retinal pigment epithelium. Mol Vis 20:73-88
Yeatman, Holly R; Lane, J Robert; Choy, Kwok Ho Christopher et al. (2014) Allosteric modulation of M1 muscarinic acetylcholine receptor internalization and subcellular trafficking. J Biol Chem 289:15856-66
Jin, Chunhua; Sun, Jingping; Stilphen, Carly A et al. (2014) HV1 acts as a sodium sensor and promotes superoxide production in medullary thick ascending limb of Dahl salt-sensitive rats. Hypertension 64:541-50
Lambert, Nevin A; Javitch, Jonathan A (2014) Rebuttal from Nevin A. Lambert and Jonathan A. Javitch. J Physiol 592:2449
Gavalas, Anthony; Lan, Tien-Hung; Liu, Qiuju et al. (2013) Segregation of family A G protein-coupled receptor protomers in the plasma membrane. Mol Pharmacol 84:346-52
Dong, Chunmin; Nichols, Charles D; Guo, Jianhui et al. (2012) A triple arg motif mediates ?(2B)-adrenergic receptor interaction with Sec24C/D and export. Traffic 13:857-68
Lan, Tien-Hung; Kuravi, Sudhakiranmayi; Lambert, Nevin A (2011) Internalization dissociates ?2-adrenergic receptors. PLoS One 6:e17361
Urizar, Eneko; Yano, Hideaki; Kolster, Rachel et al. (2011) CODA-RET reveals functional selectivity as a result of GPCR heteromerization. Nat Chem Biol 7:624-30
Johnston, Jennifer M; Aburi, Mahalaxmi; Provasi, Davide et al. (2011) Making structural sense of dimerization interfaces of delta opioid receptor homodimers. Biochemistry 50:1682-90

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