G-protein-coupled receptor dimerization: modulation of receptor function

Rios, Carl; Jordan, Bryen A.; Gomes, Ivone; Devi, Lakshmi A.

doi:10.1016/s0163-7258(01)00160-7

Cited by 298 publications

(251 citation statements)

References 110 publications

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“…In contrast, multiple subtypes of nuclear steroid receptors are present in the brain and gonads and have overlapping distributions in certain regions (23,24) and, therefore, have the potential to form heterodimers. GPCRs also form dimers that may be important for receptor activation (25,26). However, the formation of heterodimers among the mPR subtypes is unlikely in most human tissues based on the distributions of their mRNAs.…”

Section: Discussionmentioning

confidence: 99%

Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor

Zhu

Bond

Thomas

2003

Proc. Natl. Acad. Sci. U.S.A.

645

470

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Recently we discovered a previously uncharacterized gene with the characteristics of a membrane progestin receptor (mPR) in a fish model, spotted seatrout. Here, we report the identification, cloning, and characteristics of other members of this hitherto unknown family of putative mPRs from several vertebrate species, including human, mouse, pig, Xenopus, zebrafish, and Fugu, with highly conserved nucleotide and deduced amino acid sequences and similar structures to the spotted seatrout mPR. The 13 vertebrate genes identified seem to belong to an unknown gene family. Phylogenetic analysis indicates these cDNAs comprise three distinct groups (named ␣, ␤, and ␥) within this gene family. Structural analyses of the translated cDNAs suggest they encode membrane proteins with seven transmembrane domains. The transcript sizes of the human ␣, ␤, and ␥ putative mPR mRNAs varied from 2.8 to 5.8 kb and showed distinct distributions in reproductive, neural, kidney and intestinal tissues, respectively. Recombinant human ␣, ␥, and mouse ␤ proteins produced in an Escherichia coli expression system demonstrated high affinity (Kd ‫؍‬ 20 -30 nM) saturable binding for progesterone. Further analysis of binding to the ␥-subtype revealed binding was specific for progestins and was displaceable, with rapid rates of association and dissociation (t1/2 ‫؍‬ 2-8 min). These results suggest this is a new family of steroid receptors unrelated to nuclear steroid receptors, but instead having characteristics of G protein-coupled receptors.A lthough the existence of specific receptors on the surface of target cells mediating rapid nongenomic actions of steroids was recognized 20 years ago (1, 2), efforts to determine the structures of steroid membrane receptors have been unsuccessful until now (3-5). In the accompanying paper in this issue of PNAS (6), we described a gene discovered in a teleost species, spotted seatrout, whose protein fulfils the criteria for its designation as a steroid membrane receptor, including structural plausibility, specific tissue and plasma membrane localization, steroid binding characteristic of steroid and progestin receptors, coupling to second messenger pathways, regulation by steroid hormones, and biological relevance. Evidence was obtained that this progestin membrane receptor (mPR) is the intermediary in progestin induction of oocyte meiotic maturation in teleost fishes and activates an inhibitory G protein (G i/o ), which suggests it may be a G protein-coupled receptor (GPCR).The aims of this study were to search for related cDNA fragments of other vertebrates in the genomic databases, clone and sequence their full-length cDNAs, and partially characterize these genes and their recombinant proteins. This paper reports the identification of 13 additional vertebrate genes closely related to the spotted seatrout mPR. Structural and phylogenetic evidence is presented that these vertebrate genes encode for membrane proteins with seven or occasionally six transmembrane domains that can be classified into three subty...

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Section: Discussionmentioning

confidence: 99%

Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor

Zhu

Bond

Thomas

2003

Proc. Natl. Acad. Sci. U.S.A.

645

470

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“…Given the predominance of heptaspanning membrane receptors as dimers (see [4][5][6][7][8][9][10][11][12][13][14][15] for an extensive review), the interpretation of complex binding using a receptor dimer model might be more straightforward. In this case positive or negative cooperativity is naturally explained by assuming, like in the case of the enzymes, that 4 binding of the first ligand to the dimer modifies the equilibrium parameters of binding of the second ligand molecule to the dimer.…”

Section: Introductionmentioning

confidence: 99%

Useful pharmacological parameters for G-protein-coupled receptor homodimers obtained from competition experiments. Agonist–antagonist binding modulation

Casadó

Ferrada

Bonaventura

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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“…With the advent of very sensitive fluorescence technologies (Hovius et al 2000), new approaches to study G-protein-coupled receptor (GPCR) structure (Chollet and Turcatti 1999), trafficking (Kallal and Benovic 2000;Gicquiaux et al 2002) and signalling (Milligan 1999), as well as GPCR-protein (Angers et al 2000;Rios et al 2001) and GPCR-ligand (Chollet and Turcatti 1999;Vollmer et al 1999;Ghanouni et al 2001;Palanché et al 2001;Valenzuela-Fernandez et al 2001) interactions, have been developed.…”

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confidence: 99%

Fluorescence resonance energy transfer to probe human M1 muscarinic receptor structure and drug binding properties

Ilien

Franchet

Bernard

et al. 2003

Journal of Neurochemistry

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Human M1 muscarinic receptor chimeras were designed (i) to allow detection of their interaction with the fluorescent antagonist pirenzepine labelled with Bodipy [558/568], through fluorescence resonance energy transfer, (ii) to investigate the structure of the N-terminal extracellular moiety of the receptor and (iii) to set up a fluorescence-based assay to identify new muscarinic ligands. Enhanced green (or yellow) fluorescent protein (EGFP or EYFP) was fused, through a linker, to a receptor N-terminus of variable length so that the GFP barrel was separated from the receptor first transmembrane domain by six to 33 amino-acids. Five fluorescent constructs exhibit high expression levels as well as pharmacological and functional properties superimposable on those of the native receptor. Bodipy-pirenzepine binds to the chimeras with similar kinetics and affinities, indicating a similar mode of interaction of the ligand with all of them. From the variation in energy transfer efficiencies determined for four different receptor-ligand complexes, relative donor (EGFP)-acceptor (Bodipy) distances were estimated. They suggest a compact architecture for the muscarinic M1 receptor amino-terminal domain which may fold in a manner similar to that of rhodopsin. Finally, this fluorescence-based assay, prone to miniaturization, allows reliable detection of unlabelled competitors.

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G-protein-coupled receptor dimerization: modulation of receptor function

Cited by 298 publications

References 110 publications

Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor

Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor

Useful pharmacological parameters for G-protein-coupled receptor homodimers obtained from competition experiments. Agonist–antagonist binding modulation

Fluorescence resonance energy transfer to probe human M1 muscarinic receptor structure and drug binding properties

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