Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

Prinster, Steven C.; Hague, Chris; Hall, Randy A.

doi:10.1124/pr.57.3.1

Cited by 337 publications

(277 citation statements)

References 136 publications

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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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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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“…cases for the maturation of receptor complexes that may exhibit pharmacological, signaling, and turnover properties that distinguish them from their homomeric equivalents (6)(7)(8). Although these exciting observations have illuminated novel opportunities for therapeutic manipulation (9), much remains to be learned of how GPCR interactions are regulated both structurally and functionally.…”

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confidence: 99%

Secretin Receptor Oligomers Form Intracellularly during Maturation through Receptor Core Domains

Lisenbee

Miller

2006

Biochemistry

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Oligomerization of numerous G protein-coupled receptors has been documented, including the prototypic family B secretin receptor. The clinical significance of oligomerization of this receptor became clear with the recent observation that a misspliced form present in pancreatic cancer could associate with the wild type receptor and act as a dominant negative inhibitor of its normal growth inhibitory function. Our goal was to explore the molecular mechanism of this interaction using bioluminescence (BRET) and fluorescence (FRET) resonance energy transfer and fluorescence microscopy with a variety of receptor constructs tagged with luciferase or cyan or yellow fluorescent proteins. BRET signals comparable to those obtained from cells coexpressing differentially-tagged wild type receptors were observed for similarly-tagged secretin receptors in which all or part of the amino-terminal domain was deleted. As expected, neither of these constructs bound secretin, and only the partially truncated construct sorted to the plasma membrane. Receptors lacking the majority of the carboxyl-terminal domain, including that important for phosphorylation-mediated desensitization, also produced BRET signals above background. These findings suggested that the receptor's membrane-spanning core is responsible for secretin receptor oligomerization. Interestingly, alanine substitutions for a -GxxxG-helix interaction motif in transmembrane segment seven created non-functional receptors that were capable of forming oligomers. Furthermore, treatment of receptor-expressing cells with brefeldin A did not eliminate the BRET signals, and morphologic FRET experiments confirmed the expected subcellular localizations of receptor oligomers. We conclude that secretin receptor oligomerization occurs through -GxxxG-motifindependent interactions of transmembrane segments during the maturation of nascent molecules.Quaternary assemblies of G protein-coupled, plasma membrane-bound heptahelical receptors (GPCRs) 1 appear to be a common structural feature of these functionally diverse, pharmacologically important molecules. In most cases, however, it has been particularly difficult to determine the stoichiometry of association, such that the general term "oligomerization" is most appropriate for describing quaternary assemblies that have been characterized only partially. Such assemblies have been documented for numerous family A, family B and family C GPCRs as homomeric associations of receptors with themselves or as heteromeric associations of receptors with structurally-related family members (1-3). Functional characterizations of known receptor oligomers have demonstrated that these assemblies are important modulators of receptor maturation, ligand-binding specificity, and downstream signaling processes (4,5). Interestingly, heteromer formation is required in some † This work was supported by grants from the National Institutes of Health (DK46577) and the Fiterman Foundation.* To whom correspondence should be addressed: Mayo Clinic, 13400 E. She...

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“…The functional role of such supra-molecular complexes is still unclear and may vary depending on the GPCR type [18,20]. In particular, for TP, the formation of TPa-TPb and TPa-IP heterodimers in constitutive human systems seems to greatly influence their pharmacological profiles [4][5][6], whereas no data are yet available on the functional significance of TP homodimerization.…”

Section: Discussionmentioning

confidence: 99%

“…The conformational changes transmitted by direct proteinprotein interactions may represent a first level of regulation of a receptor. The biological role(s) of homologous and heterologous receptor aggregation is/are, however, far from being clarified [18][19][20]. Likewise, knowledge about the most likely architectures of GPCR dimers is still illdefined.…”

Section: Introductionmentioning

confidence: 99%

Light on the structure of thromboxane A2 receptor heterodimers

Fanelli

Mauri

Capra

et al. 2011

Cell. Mol. Life Sci.

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The structure-based design of a mutant form of the thromboxane A 2 prostanoid receptor (TP) was instrumental in characterizing the structural determinants of the hetero-dimerization process of this G protein coupled receptor (GPCR). The results suggest that the heterodimeric complexes between the TPa and b isoforms are characterized by contacts between hydrophobic residues in helix 1 from both monomers. Functional characterization confirms that TPa-TPb hetero-dimerization serves to regulate TPa function through agonist-induced internalization, with important implications in cardiovascular homeostasis. The integrated approach employed in this study can be adopted to gain structural and functional insights into the dimerization/oligomerization process of all GPCRs for which the structural model of the monomer can be achieved at reasonable atomic resolution.

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Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance

Cited by 337 publications

References 136 publications

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

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

Secretin Receptor Oligomers Form Intracellularly during Maturation through Receptor Core Domains

Light on the structure of thromboxane A2 receptor heterodimers

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