The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components
Open accessAbstract
G protein-coupled receptors (GPCRs) oligomerization has emerged as a vital characteristic of receptor structure. Substantial experimental evidence supports the existence of GPCR-GPCR interactions in a coordinated and cooperative manner. However, despite the current development of experimental techniques for large-scale detection of GPCR heteromers, in order to understand their connectivity it is necessary to develop novel tools to study the global heteroreceptor networks. To provide insight into the overall topology of the GPCR heteromers and identify key players, a collective interaction network was constructed. Experimental interaction data for each of the individual human GPCR protomers was obtained manually from the STRING and SCOPUS databases. The interaction data were used to build and analyze the network using Cytoscape software. The network was treated as undirected throughout the study. It is comprised of 156 nodes, 260 edges and has a scale-free topology. Connectivity analysis reveals a significant dominance of intrafamily versus interfamily connections. Most of the receptors within the network are linked to each other by a small number of edges. DRD2, OPRM, ADRB2, AA2AR, AA1R, OPRK, OPRD and GHSR are identified as hubs. In a network representation 10 modules/clusters also appear as a highly interconnected group of nodes. Information on this GPCR network can improve our understanding of molecular integration. GPCR-HetNet has been implemented in Java and is freely available at http://www.iiia.csic.es/~ismel/GPCR-Nets/index.html.
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GPCR heteroreceptor complexes exert allosteric receptor-receptor interactions that modulate the recognition, signaling, and trafficking of the participating receptor protomers.
“These complexes exert allosteric receptor–receptor interactions that modulate the recognition, signaling, and trafficking of the participating receptor protomers, thereby influencing other associated proteins (Fuxe et al., 2010; Borroto-Escuela et al., 2014; Fuxe et al., 2014; Borroto-Escuela et al., 2015b; Fuxe and Borroto-Escuela, 2016; Borroto-Escuela et al., 2017a).”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as Borroto-Escuela et al., 2014
GPCR heteroreceptor complexes (dimers or higher order complexes) via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers.
“An important integrative molecular mechanism in the cellular plasma membrane is represented by GPCR heteroreceptor complexes (dimers or higher order complexes) that via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers with an impact on other participating proteins”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Borroto-Escuela et al., 2014
Computational approaches for modeling and predicting GPCR dimerization have been provided by the GGIP web server and online resources including the GPCR-HetNet.
“Computational approaches for modeling and predicting GPCR dimerization have been provided by the GGIP web server (Nemoto et al., 2022) and online resources including the GPCR-HetNet (Borroto-Escuela et al., 2014).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Borroto-Escuela et al., 2014
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References 87 · Cited by 134
- Authors
- Borroto-Escuela, D., Brito, I., Romero-Fernandez, W., Di Palma, M., Oflijan, J., Skieterska, K., Duchou, J., Van Craenenbroeck, K., Suárez-Boomgaard, D., Rivera, A., Guidolin, D., Agnati, L., & Fuxe, K.
- Affiliations
- Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden
- Consejo Superior de Investigaciones Científicas (ES)
- University of Tartu (EE)
- Ghent University (BE)
- Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Ghent University, 9000 Ghent, Belgium
- Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain
- Universidad de Málaga (ES)
- University of Padua (IT)
- Karolinska Institutet (SE)
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2014-05-14
- Volume
- 15
- Issue
- 5
- Pages
- 8570-8590
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC4057749
- OpenAlex
- W2106588046
- Cited by
- 134
- References
- 87
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 12 · 2022: 15 · 2021: 14 · 2020: 9 · 2019: 17 · 2018: 22 · 2017: 10 · 2016: 15 · 2015: 8 · 2014: 5
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- Hjärnfonden (04X-715)
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- G protein-coupled receptors, receptor oligomerization, protein-protein interaction network, network topology, scale-free networks, hub proteins, DRD2, OprM, ADRB2, OprD, growth hormone secretagogue receptor, network clustering
- MeSH terms
- Algorithms, Humans, Models, Molecular, User-Computer Interface, Cluster Analysis, Dimerization, Internet, Databases, Protein, Receptors, G-Protein-Coupled, Metabolic Networks and Pathways
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