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

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 ARTICLESThis 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 Abbreviations 7TM, 7 transmembrane segment; AgRP, agouti-related peptide; AMPK, AMP-activated PK; AP2, adaptor-related protein complex 2; AT1A receptor, angiotensin 1A receptor; AVP, arginine-vasopressin; CREB, cAMP response element binding protein; ECL, extracellular loop; FAS, fatty acid synthase; GH, growth hormone; GHS, growth hormone secretagogues; GRK, GPCR kinase; IP, inositol phosphate; IP3, inositol tris-1,4,5-phosphate; Isn, isonipecotic acid; MC4, melanocortin 4; NPY, neuropeptide Y; SRE, serum response element; UCP2, uncoupling protein 2; VTA, ventral tegmental area; WT, wild type Introduction to ghrelin receptor physiologyThe ghrelin receptor, previously known as the growth hormone secretagogue (GHS) receptor 1a (for receptor nomenclature see Alexander et al., 2011), is the receptor for the anabolic hormone ghrelin. This receptor is involved in GH secretion, appetite regulation, fat accumulation and energy expenditure. In addition it can also modulate behaviour and mood (van der Lely et al., 2004; Dickson et al., 2011; Figure 1). GHThe ghrelin receptor was initially cloned as a receptor important for GH secr...

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