The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components

Abstract

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.

Figure 1.

GPCR HetNet graph. Color code: blue, Family 1 or Class A; red, Family 2 or Class B; orange, Family 3 or Class C.

Figure 2.

Topological properties distributions. In (A) and (B) we present the node degree distribution and clustering coefficient distribution for the GPCR receptor–receptor interaction network, respectively. The network shows power-law node degree and clustering coefficient distributions (see Table 3 for further details). Axes are plotted on logarithmic scale. In (C) we show the path length distribution of the GPCR-HetNet.

Figure 3.

Hubs identified according to different criteria (“top 95% of the high degree nodes” and “node degree > 8”) are shown in blue.

Figure 4.

GPCR-HetNet motifs. Nine clusters identified using the MCODE search algorithms are represented and rank ordered, from top left to right down, according to their density (inter-connectivity) and size (number of protomers).