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Int. J. Mol. Sci. 2014, 15(5), 8570-8590;

The G Protein-Coupled Receptor Heterodimer Network (GPCR-HetNet) and Its Hub Components

Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden
IIIA-CSIC, Artificial Intelligence Research Institute, Spanish National Research Council, 08193 Barcelona, Spain
Department of Earth, Life and Environmental Sciences, Section of Physiology, Campus Scientifico Enrico Mattei, Urbino 61029, Italy
Department of Physiology, Faculty of Medicine, University of Tartu, Tartu 50411, Estonia
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
Department of Molecular Medicine, University of Padova, Padova 35121, Italy
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 19 December 2013 / Revised: 26 March 2014 / Accepted: 30 April 2014 / Published: 14 May 2014
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
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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 View Full-Text
Keywords: G protein-coupled receptors; network; heterodimerization; heteromers; dimerization; oligomerization; hubs; receptor–receptor interactions; clusters; architecture G protein-coupled receptors; network; heterodimerization; heteromers; dimerization; oligomerization; hubs; receptor–receptor interactions; clusters; architecture

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Borroto-Escuela, D.O.; 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.F.; Fuxe, K. The G Protein-Coupled Receptor Heterodimer Network (GPCR-HetNet) and Its Hub Components. Int. J. Mol. Sci. 2014, 15, 8570-8590.

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