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Review
. 2013 Dec;170(7):1349-62.
doi: 10.1111/bph.12361.

Functionally biased signalling properties of 7TM receptors - opportunities for drug development for the ghrelin receptor

B Sivertsen  1 , N Holliday, A N Madsen, B Holst
Affiliations
Review

Functionally biased signalling properties of 7TM receptors - opportunities for drug development for the ghrelin receptor

B Sivertsen et al. Br J Pharmacol. 2013 Dec.

Abstract

The ghrelin receptor is a 7 transmembrane (7TM) receptor involved in a variety of physiological functions including growth hormone secretion, increased food intake and fat accumulation as well as modulation of reward and cognitive functions. Because of its important role in metabolism and energy expenditure, the ghrelin receptor has become an important therapeutic target for drug design and the development of anti-obesity compounds. However, none of the compounds developed so far have been approved for commercial use. Interestingly, the ghrelin receptor is able to signal through several different signalling pathways including Gαq , Gαi/o , Gα12/13 and arrestin recruitment. These multiple signalling pathways allow for functionally biased signalling, where one signalling pathway may be favoured over another either by selective ligands or through mutations in the receptor. In the present review, we have described how ligands and mutations in the 7TM receptor may bias the receptors to favour either one G-protein over another or to promote G-protein independent signalling pathways rather than G-protein-dependent pathways. For the ghrelin receptor, both agonist and inverse agonists have been demonstrated to signal more strongly through the Gαq -coupled pathway than the Gα12/13 -coupled pathway. Similarly a ligand that promotes Gαq coupling over Gαi coupling has been described and it has been suggested that several different active conformations of the receptor may exist dependent on the properties of the agonist. Importantly, ligands with such biased signalling properties may allow the development of drugs that selectively modulate only the therapeutically relevant physiological functions, thereby decreasing the risk of side effects.

Linked articles: This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

Keywords: 7TM receptor; GPCR; biased agonism; biased signalling; ghrelin receptor.

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Figures

Figure 1
Figure 1
Cartoon of the most well-known ghrelin-mediated physiological functions.
Figure 2
Figure 2
Multiple signalling pathways of the ghrelin receptor. Dotted arrows represent not fully verified signalling pathways, and black full arrows indicate pathways that have been described or suggested for the ghrelin receptor. The ghrelin receptor is able to signal through three different G-proteins, for example Gαq, Gαi/o, Gα12/13 in addition to G–protein-independent arrestin coupling and internalization. Gαq, that activates PLC and leads to increased IP and DAG formation can induce an increase in Ca2+ signalling. However, the pharmacological profiling of different ghrelin receptor agonists indicates that the Ca2+ signalling and IP accumulation originate from separate signalling pathways (Holst et al., 2005), which explains the dotted line. In addition, Gαq coupling may also lead to CRE-mediated transcription activity and probably contributes to the SRE-mediated transcriptional activity. Finally, ligand-mediated Gαq coupling may also stimulate ERK1/2 phosphorylation. Gα12/13 activates RhoA and ROCK resulting in SRE transcription. Gαi/o, generally inhibits adenylate cylase to decrease cAMP accumulation; however, this has not been shown for the ghrelin receptor and it is possible that it can couple to Gαi/o and induce Ca2+ release. Ligand activation of the ghrelin receptor induces recruitment of β-arrestin, which might lead to receptor internalization. Both the constitutive and ligand activation of the receptor induce internalization of the receptor. β-Arrestins might lead to ERK phosphorylation but this is still uncertain.
Figure 3
Figure 3
Dose–response curves of an example of an unbiased agonist, a biased agonist and a biased inverse agonist. The dose–response curve was performed in HEK293 cells transiently transfected with the ghrelin receptor where the response of the ligands is measured by the accumulation of IP (Gαq coupled) and by activation of SRE-mediated transcriptional control (Gα12/13 mediated; Holst et al., 2006). Dose–response curves for (A) the un-biased ligand, ghrelin, (B) the biased agonist, wFw-Isn and (C) the biased inverse agonist are shown.
Figure 4
Figure 4
The effects of two different biased agonists. (A) The biased agonist JMV3018 is able to stimulate Gαq recruitment in purified ghrelin receptors in lipid discs, but no recruitment of Gαq or arrestin was observed for this compound. (B) The biased agonist wFw-Isn is able to couple to Gαq and the downstream signalling pathways IP and ERK phophorylation, but it is unable to activate the Gα12/13 coupled SRE pathway when compared with ghrelin.
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