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Translating biased signaling in the ghrelin receptor system into differential in vivo functions.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Oct 23; Vol. 115 (43), pp. E10255-E10264. Date of Electronic Publication: 2018 Oct 09. - Publication Year :
- 2018
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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 Gα <subscript>q/11</subscript> and Gα <subscript>12</subscript> 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 Gα <subscript>q/11</subscript> was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gα <subscript>q/11</subscript> , without antagonism at β-arrestin or other G-protein coupling is sufficient to decrease food intake.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Eating drug effects
GTP-Binding Proteins metabolism
HEK293 Cells
Humans
Ligands
Male
Mice
Piperidines pharmacology
Quinazolinones pharmacology
Rats
Rats, Sprague-Dawley
Signal Transduction drug effects
Signal Transduction physiology
beta-Arrestins metabolism
Ghrelin metabolism
Receptors, Ghrelin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 43
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 30301804
- Full Text :
- https://doi.org/10.1073/pnas.1804003115