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Review
. 2009 Dec;10(6):559-69.
doi: 10.2174/138920309789630606.

Theoretical considerations on the topological organization of receptor mosaics

Agnati Luigi Francesco  1 , Fuxe Kjell, Woods Amina, Genedani Susanna, Guidolin Diego
Affiliations
Review

Theoretical considerations on the topological organization of receptor mosaics

Agnati Luigi Francesco et al. Curr Protein Pept Sci. 2009 Dec.

Abstract

The concept of Receptor Mosaic (RM) is discussed; hence the integrative functions of the assemblage of G-protein coupled receptors physically interacting in the plane of the plasma membrane. The main focus is on a hetero-trimer of G-protein coupled receptors, namely the A2A-D2-CB1 receptor trimer. A bioinformatics analysis was carried out on the amino acid sequence of these receptors to indicate domains possibly involved in the receptor-receptor interactions. Such a bioinformatic analysis was also carried out on the RM formed by mGLU R5, D2 and A2A. The importance of topology, i.e., of the reciprocal localisation of the three interacting receptors in the plan of the membrane for the RM integrative functions is underlined. However, it is also pointed out that this fundamental aspect still waits techniques capable of an appropriate investigation. Finally, it is discussed how RM topology can give hints for a structural definition of the concept of hub receptor. Thus, just as in any network, the receptor operating as a hub is the one that in the molecular network formed by the receptors has the highest number of inputs.

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Figures

Fig. (1)
Fig. (1)
Schematic representation of the sites of GPCR-GPCR interactions [27]. Recent evidence [29, 30] has given a support to all these types of interactions, which could have different chemical characteristics, e.g., different stability and rigidity and hence different functional meanings. For further details see text.
Fig. (2)
Fig. (2)
Schematic representation of a GPCR as a multi-domain protein, which is embedded into three micro-environments: the extra-cellular space (ECS), the plasma membrane (M) and the intra-cellular space (ICS). It is proposed that two regions (‘a’ and ‘b’) can be distinguished in a GPCR , namely a rather rigid core and a more plastic surrounding, respectively. The possible mechanisms for the RRI are also indicated. The chemico-physical features of the three environments as well as the action of allosteric modulators can affect both the conformation and/or the size of ‘a’ and ‘b’ regions and the mechanisms of RRI.
Fig. (3)
Fig. (3)
Schematic representation of the possible Receptor-Receptor Interactions. Two main case are illustrated: the interface/interface interactions and the ligand (promontory)/pocket (gulf) interactions. For further details, see text.
Fig. (4)
Fig. (4)
Two main models have been suggested by Gouldson [35] for the formation of GPCR dimers: the “domain swapping” and the “domain contact”. According to Gouldson it is possible to distinguish two pseudo-independent units in the GPCR. Thus, the N-terminus and helices 1-5 constitute the A-GPCR domain, while helices 6 and 7 through to the C-terminus constitute the B-GPCR domain. A and B domains are connected by a hinge loop (third intracellular loop: ICL3), which is frequently the longest loop in GPCRs and therefore very well suited to allow reciprocal movements of the two A- and B-GPCR domains. Even considering only contact 5-6 dimers and swapped 5-6 dimers three basic models can occur: pure swapping, pure contact, and mixed model (contact and swapping). These models are shown in the scheme of the Figure [13].
Fig. (5)
Fig. (5)
Schematic illustration of the heuristic relevance of the integrative action of a hetero-trimer to have hints on its topology. The upper two panels illustrate the limits of the chemical and biophysical approaches in allowing a precise determination of the localisation (topology) of receptors within a RM. For further details, see text.
Fig. (6)
Fig. (6)
Schematic illustration of the possible feed-back circulation of the information in a triangular trimeric RM. It should be noticed that all receptors have two sites allowing RRIs, hence the flow of the information. For further details, see text.
Fig. (7)
Fig. (7)
Possible topological arrangement of the trimeric RM formed by CB1, A2A and D2. The hypothetical topology is based on Table 1. and on the plot and the inserted table of Fig. 7. For further details, see text.
Fig. (8)
Fig. (8)
Per-residue analysis of D2-ICL3 (163 AA). The plot clearly indicates the region where disordered sequences are present. These sequences are precisely given in the inserted table. For further details, see text.
Fig. (9)
Fig. (9)
Some possible topological arrangements of A2A D2 CB1 as building blocks of high-order receptor mosaics. For further details, see text.
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