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

Authors

  • B Sivertsen,

    1. Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, the Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • N Holliday,

    1. Cell Signalling Research Group, School of Biomedical Sciences, University of Nottingham, The Medical School, Nottingham, UK
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  • A N Madsen,

    1. Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, the Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • B Holst

    Corresponding author
    1. Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, the Panum Institute, University of Copenhagen, Copenhagen, Denmark
    • Correspondence

      Birgitte Holst, Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, the Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark. E-mail: holst@sund.ku.dk

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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

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