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G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.

ABSTRACT: Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.

SUBMITTER: Ferre S

PROVIDER: S-EPMC3973609 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.

Ferré Sergi S Casadó Vicent V Devi Lakshmi A LA Filizola Marta M Jockers Ralf R Lohse Martin J MJ Milligan Graeme G Pin Jean-Philippe JP Guitart Xavier X

Pharmacological reviews 20140210 2

Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It sti ...[more]

PMID: 24515647

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Project description:BackgroundPrevious studies have demonstrated that seven transmembrane receptors (7TM-Rs) can associate with various chaperones to control their maturation and export. It has been shown for a few years now that 7TM-Rs can form homo or heterooligomeric complexes. Due to the difficulty to study heterooligomers in a context devoid of homooligomers signaling, very little is known on heterooligomerization. β2AR-AT1R receptor complexes have been found on cells and ligand activation of one receptor affects signaling of the partner. Yet, very little is known about the mechanisms linking those receptors together. We propose to examine the role of chaperones in the maturation of homo- and heterodimers of the β2AR and AT1R. It would not be surprising that strict cellular mechanisms exist to ensure that only properly folded receptors are inserted into the plasma membrane.ResultsOur goal is to understand the process whereby the adrenergic and angiotensin receptors attain their proper mature conformation. We determined whether any of the common chaperones are physically associated with the fully and/or immature β2AR and AT1R receptors forms and if they play any role in the selective recruitment of G proteins subunits to receptor complexes. Our results suggest that when a pair of receptors is expressed in such way that one is retained in the endoplasmic reticulum (ER), this immature receptor will dictate the chaperones interacting with the receptor complex. We showed that ERp57 is important for receptor dimerization of AT1R homo and β2AR/AT1R receptor dimers, but plays no role in the β2AR homodimerization. Then, we verified if some of those chaperones could play a role in the assembly of the heterotrimeric G protein subunits with the receptor complex, but none appeared to be essential.ConclusionsOverall, our results suggest that variations among receptor oligomers occur early in the synthesis/maturation processes, and that chaperones will interact more specifically with some receptor pairs than others to allow the formation of certain receptor pairs, while others will contribute to the folding and maturation of receptors without any effect on receptor assembly within a signaling complex.

Project description:Estrogens play a critical role in many aspects of physiology, particularly female reproductive function, but also in pathophysiology, and are associated with protection from numerous diseases in premenopausal women. Steroids and the effects of estrogen have been known for ?90 years, with the first evidence for a receptor for estrogen presented ?50 years ago. The original ancestral steroid receptor, extending back into evolution more than 500 million years, was likely an estrogen receptor, whereas G protein-coupled receptors (GPCRs) trace their origins back into history more than one billion years. The classical estrogen receptors (ER? and ER?) are ligand-activated transcription factors that confer estrogen sensitivity upon many genes. It was soon apparent that these, or novel receptors may also be responsible for the "rapid"/"non-genomic" membrane-associated effects of estrogen. The identification of an orphan GPCR (GPR30, published in 1996) opened a new field of research with the description in 2000 that GPR30 expression is required for rapid estrogen signaling. In 2005-2006, the field was greatly stimulated by two studies that described the binding of estrogen to GPR30-expressing cell membranes, followed by the identification of a GPR30-selective agonist (that lacked binding and activity towards ER? and ER?). Renamed GPER (G protein-coupled estrogen receptor) by IUPHAR in 2007, the total number of articles in PubMed related to this receptor recently surpassed 1000. In this article, the authors present personal perspectives on how they became involved in the discovery and/or advancement of GPER research. These areas include non-genomic effects on vascular tone, receptor cloning, molecular and cellular biology, signal transduction mechanisms and pharmacology of GPER, highlighting the roles of GPER and GPER-selective compounds in diseases such as obesity, diabetes, and cancer and the obligatory role of GPER in propagating cardiovascular aging, arterial hypertension and heart failure through the stimulation of Nox expression.

Dataset Information

G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.

Publications

G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.

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