GPCR-OKB: the G Protein Coupled Receptor Oligomer Knowledge Base

Khelashvili, George; Dorff, Kevin C.; Shan, Jufang; Camacho‐Artacho, Marta; Skrabanek, Lucy; Vroling, Bas; Bouvier, Michel; Devi, Lakshmi A.; George, Susan R.; Javitch, Jonathan A.; Lohse, Martin J.; Milligan, Graeme; Neubig, Richard R.; Palczewski, Krzysztof; Parmentier, Marc; Pin, Jean‐Philippe; Vriend, Gerrit; Campagne, Fabien; Filizola, Marta

doi:10.1093/bioinformatics/btq264

Cited by 69 publications

(47 citation statements)

References 10 publications

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“…They are mostly stored in the GPCR Oligomerization Knowledge Base (http://www.gpcr-okb. org; Khelashvili et al, 2010) and, for what it concerns the heteromers, in the GPCR-HetNet (http://www.iiia.csic. es/∼ismel/GPCR-Nets/index.html; Borroto-Escuela et al, 2014) containing more than 500 entries.…”

Section: Introductionmentioning

confidence: 99%

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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Abstract:The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

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Section: Introductionmentioning

confidence: 99%

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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“…Over the last 20 years, dimerization and/or oligomerization was reported for nearly all tested GPCR subtypes using mostly engineered GPCR constructs expressed in heterologous systems ( Fig. 1) (Khelashvili et al, 2010;Cottet et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

Vischer

Castro

2015

Mol Pharmacol

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Heteromerization of G protein-coupled receptors (GPCRs) can significantly change the functional properties of involved receptors. Various biochemical and biophysical methodologies have been developed in the last two decades to identify and functionally evaluate GPCR heteromers in heterologous cells, with recent approaches focusing on GPCR complex stoichiometry and stability. Yet validation of these observations in native tissues is still lagging behind for the majority of GPCR heteromers. Remarkably, recent studies, particularly some involving advanced fluorescence microscopy techniques, are contributing to our current knowledge of aspects that were not well known until now, such as GPCR complex stoichiometry and stability. In parallel, a growing effort is being applied to move the field forward into native systems. This short review will highlight recent developments to study the stoichiometry and stability of GPCR complexes and methodologies to detect native GPCR dimers.

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“…With the exception of family C GPCRs, where obligate dimerization can occur (4), the role of oligomerization in GPCR function has remained controversial (2)(3)(4)(5)(6)(7)(8), and this has been the subject of a number of recent reviews (9)(10)(11). Although there is an increasing body of evidence supporting dimerization of GPCRs as a widespread feature of GPCR biology, including numerous studies on family A GPCRs, whether these are stable, transient, constitutive, or ligand dependent, and how they impact on receptor function and drug discovery are less clear, and general rules for oligomeric behavior are not evident (9)(10)(11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

“…Although there is an increasing body of evidence supporting dimerization of GPCRs as a widespread feature of GPCR biology, including numerous studies on family A GPCRs, whether these are stable, transient, constitutive, or ligand dependent, and how they impact on receptor function and drug discovery are less clear, and general rules for oligomeric behavior are not evident (9)(10)(11)(12)(13)(14)(15)(16). Even where effects on signaling are studied, these are generally linked to a single pathway and the role of dimerization in the control of receptor engagement and preference for distinct intracellular signaling intermediates (i.e., signal bias) is virtually unstudied.…”

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confidence: 99%

Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

Harikumar

Wootten

Pinon

et al. 2012

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

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The glucagon-like peptide-1 receptor (GLP-1R) is a family B G proteincoupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent highaffinity binding to GLP-1(7-36)NH 2 but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design.allosteric modulation | biased signaling | G protein-coupled receptors | family B GPCRs G protein-coupled receptors (GPCRs) are the largest superfamily of cell surface proteins and play crucial roles in virtually every physiological process. Their widespread abundance, yet selective distribution, and ability to couple to a variety of signaling and effector systems make them extremely attractive targets for drug development (1). Recently, there has been increasing interest in the stoichiometry of receptors involved in GPCR signaling complexes and how this may impact on receptor function and drug discovery (2-4).With the exception of family C GPCRs, where obligate dimerization can occur (4), the role of oligomerization in GPCR function has remained controversial (2-8), and this has been the subject of a number of recent reviews (9-11). Although there is an increasing body of evidence supporting dimerization of GPCRs as a widespread feature of GPCR biology, including numerous studies on family A GPCRs, whether these are stable, transient, constitutive, or ligand dependent, and how they impact on receptor function and drug discovery are less clear, and general rules for oligomeric behavior are not evident (9-16). Even where effects on signaling are studied, these are generally linked to a single pathway and the role of dimerization in the control of receptor engagement and preference for distinct intracellular signaling intermediates (i.e., signal bias) is virtually unstudied.For family B GPCRs, which encompass many ther...

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GPCR-OKB: the G Protein Coupled Receptor Oligomer Knowledge Base

Abstract: The GPCR-OKB web application is freely available at http://www.gpcr-okb.org

Cited by 69 publications

References 10 publications

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

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