Oligomerization of GPCRs involved in endocrine regulation

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   Figure 1

   Putative constellations of oligomers. (A) A particular GPCR (GPCR_x) as a monomer (schematic cylinder indicates the entire receptor). (B) Two monomers of the same GPCR interacting as a homodimer. (C) Dimerization between GPCR_x with a different GPCR_y. (D) GPCR_x may potentially interact with a non-GPCR. (E) GPCR_x may also form homooligomers with different interfaces between the protomers. (F) Assuming tetrameric (or higher order) GPCR oligomers, complexes with different protomer ratios may be formed by GPCR_x and GPCR_y.
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   Figure 2

   Observed GPCR homodimer interfaces and putative heterodimer constellations. Direct GPCR protomer interfaces are assumed to be characterized at the structural level by specific side-chain interactions or close spatial distances. Interfaces between the protomers have been found under experimental conditions for different GPCRs at the region from ICL2–TMH4 (Bakker et al. 2004, Guo et al. 2005, Mancia et al. 2008), TMH5–TMH6 (George et al. 1998, Yanagawa et al. 2011, Hu et al. 2013), and TMH4–TMH5 (Gorinski et al. 2012). Furthermore, several crystal structures of dimeric GPCR complexes were previously determined, such as those from the (A) chemokine receptor CXCR4 (Wu et al. 2010) or (B) the κ-opioid receptor (OPRK1 or KOR (Wu et al. 2012)). For OPRK1, as also for determined β-1AR and opsin structures, the protomer interface is located at TMH1–TMH2 and helix 8 (B), respectively. In line with biophysical data, dimer interfaces can be also observed between TMH5-6 (as in A). As a result, heteromeric states should also be characterized by these interfaces, but between diverse protomers (C) (protomers are colored differently for visual separation). For homomers, various scenarios of spatial protomer arrangements (a combination of dimers) can be speculated (D i and ii). The identical variety of combinations may also be assumed for heteromers, which finally includes heteromers of homomers (Ferre 2015) (D iii and v). The software PyMOL (Molecular Graphics System, Version 1.3 Schrödinger, LLC) was used for structural representation.
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   Figure 3

   Schematic illustration of different signaling scenarios that potentially occur at GPCRs and GPCR oligomers in different cell types. This scheme illustrates potential scenarios that are feasible concerning receptor signaling and oligomerization in different cell types. Further diverse scenarios and levels of receptor organization are potentially probable but have not been implemented here (e.g. by heterotrimerization). Different intracellular signaling parameters in strength (arrows thin or bold) and constitution (response boxes A–G) are indicated. A particular receptor (e.g. purple) may activate diverse intracellular signaling pathways in different cell types, indicated as cell type 1 (response A) and cell type 2 (response D). In cell type 1, this receptor is capable of activating two different downstream signaling events after ligand binding. This receptor has different properties concerning binding and activation of intracellular effectors in cell type 1 as the set and amount of particular intracellular signaling determinants (e.g. G-protein subtypes or other downstream signaling molecules) differ. Moreover, in each cell type, a multitude of different GPCRs are expressed, indicated as additional green receptors in cell type 1 or of light beige color in cell type 2. These receptors activate different signaling pathways (responses B and E). In each cell type, orphan receptors with unknown ligand(s) may also occur and influence the system of interacting proteins (not shown). In cell type 1, homooligomerization of the receptors may lead to a lowered signaling (slim arrow) compared with receptor monomer signaling. Receptor oligomerization may lead to enhanced signaling as indicated for the green receptor in cell type 1 (bold arrow). Examples of such differences in signaling responses in dependency of oligomerization or monomerization have been reported in a previous study on the MC4R (Piechowski et al. 2013). Furthermore, there may be heterooligomerization of the receptors (as described for the MC4R), indicated by receptor pairs (mixed color). These interactions should lead to the activation of signaling pathways that are partially identical to each monomer, but may also result in the activation of other signaling events (response C or F). For homo- and heterooligomers, ligand binding properties are known to drastically differ to those of monomers (indicated in heterodimer cell type 2). Moreover, bivalent ligands (illustrated in cell type 2) combine particular ligands for the respective protomers, which may ultimately lead to alterations in the signaling properties of the complex (response G).
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   Figure 4

   A complex of GPCR homo-/heterodimer interaction networks. Many members of the family A GPCRs have been reported to constitute homodimers and form heteromers (examples used here for this scheme (Pfeiffer et al. 2002, Ramsay et al. 2002, Mandrika et al. 2005, Ellis et al. 2006, Rios et al. 2006, Decaillot et al. 2008, Juhasz et al. 2008, Navarro et al. 2008, Vilardaga et al. 2008, Schellekens et al. 2013, Muller et al. 2013b)). Moreover, several of the so far analyzed subjects are able to heteromerize with different GPCRs such as the ghrelin receptor (GHSR, bold letters) (Jiang et al. 2006, Rediger et al. 2009, 2011, Schellekens et al. 2013). Consequently, the spectrum of potential interaction partners widens the putative modification of physiologically relevant signaling properties in dependency on the GPCR expression pattern in a particular cell type. For a comprehensive overview of available experiments and GPCR oligomer literature, see also the ‘The G Protein Coupled Receptor-Oligomerization Knowledge Base Project’ (Khelashvili et al. 2010). This scheme demonstrates a fragmented section of reported GPCR homo- and heteromers, whereby arrows indicate interactions between monomers (Fig. 2C) or homodimers (Ferre 2015) (potentially in constellations as suggested in Fig. 2D iii, iv and v). Dotted arrows indicate potentially more and/or thus far unknown partners. GHSR, ghrelin receptor; MC3R, melanocortin-3 receptor; 5HT2C, 5-hydroxytryptamine (serotonin) receptor 2C; 5HT1B, 5-hydroxytryptamine (serotonin) receptor 1B; GPR83, G-protein-coupled receptor 83; OPRM1, Mu opioid receptor; DRD1/DRD2, dopamine-1 and dopamine-2 receptors; Cb1R, cannabinoid receptor 1.

• © 2016 Society for Endocrinology