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Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10255-E10264. doi: 10.1073/pnas.1804003115. Epub 2018 Oct 9.

Translating biased signaling in the ghrelin receptor system into differential in vivo functions.

Author information

1
Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
2
Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
3
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C IJ4, Canada.
4
Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3C IJ4, Canada.
5
Max Planck Institute for Heart and Lung Research, Johan Wolfgang Goethe University Frankfurt, 60323 Frankfurt, Germany.
6
Department of Pharmacology, Johan Wolfgang Goethe University Frankfurt, 60323 Frankfurt, Germany.
7
Centre for Molecular Medicine, Medical Faculty, Johan Wolfgang Goethe University Frankfurt, 60323 Frankfurt, Germany.
8
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C IJ4, Canada; michel.bouvier@umontreal.ca holst@sund.ku.dk.
9
Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; michel.bouvier@umontreal.ca holst@sund.ku.dk.

Abstract

Biased signaling has been suggested as a means of selectively modulating a limited fraction of the signaling pathways for G-protein-coupled receptor family members. Hence, biased ligands may allow modulation of only the desired physiological functions and not elicit undesired effects associated with pharmacological treatments. The ghrelin receptor is a highly sought antiobesity target, since the gut hormone ghrelin in humans has been shown to increase both food intake and fat accumulation. However, it also modulates mood, behavior, growth hormone secretion, and gastric motility. Thus, blocking all pathways of this receptor may give rise to potential side effects. In the present study, we describe a highly promiscuous signaling capacity for the ghrelin receptor. We tested selected ligands for their ability to regulate the various pathways engaged by the receptor. Among those, a biased ligand, YIL781, was found to activate the Gαq/11 and Gα12 pathways selectively without affecting the engagement of β-arrestin or other G proteins. YIL781 was further characterized for its in vivo physiological functions. In combination with the use of mice in which Gαq/11 was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gαq/11, without antagonism at β-arrestin or other G-protein coupling is sufficient to decrease food intake.

KEYWORDS:

appetite regulation; biased signaling; food intake; gastric emptying; ghrelin receptor

PMID:
30301804
PMCID:
PMC6205473
[Available on 2019-04-23]
DOI:
10.1073/pnas.1804003115
[Indexed for MEDLINE]

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