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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Standard

Translating biased signaling in the ghrelin receptor system into differential in vivo functions. / Mende, Franziska; Hundahl, Cecilie; Plouffe, Bianca; Skov, Louise Julie; Sivertsen, Bjørn; Madsen, Andreas Nygaard; Lückmann, Michael; Diep, Thi Ai; Offermanns, Stefan; Frimurer, Thomas Michael; Bouvier, Michel; Holst, Birgitte.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 115, Nr. 43, 2018, s. E10255-E10264.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Mende, F, Hundahl, C, Plouffe, B, Skov, LJ, Sivertsen, B, Madsen, AN, Lückmann, M, Diep, TA, Offermanns, S, Frimurer, TM, Bouvier, M & Holst, B 2018, 'Translating biased signaling in the ghrelin receptor system into differential in vivo functions', Proceedings of the National Academy of Sciences of the United States of America, bind 115, nr. 43, s. E10255-E10264. https://doi.org/10.1073/pnas.1804003115

APA

Mende, F., Hundahl, C., Plouffe, B., Skov, L. J., Sivertsen, B., Madsen, A. N., Lückmann, M., Diep, T. A., Offermanns, S., Frimurer, T. M., Bouvier, M., & Holst, B. (2018). Translating biased signaling in the ghrelin receptor system into differential in vivo functions. Proceedings of the National Academy of Sciences of the United States of America, 115(43), E10255-E10264. https://doi.org/10.1073/pnas.1804003115

Vancouver

Mende F, Hundahl C, Plouffe B, Skov LJ, Sivertsen B, Madsen AN o.a. Translating biased signaling in the ghrelin receptor system into differential in vivo functions. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(43):E10255-E10264. https://doi.org/10.1073/pnas.1804003115

Author

Mende, Franziska ; Hundahl, Cecilie ; Plouffe, Bianca ; Skov, Louise Julie ; Sivertsen, Bjørn ; Madsen, Andreas Nygaard ; Lückmann, Michael ; Diep, Thi Ai ; Offermanns, Stefan ; Frimurer, Thomas Michael ; Bouvier, Michel ; Holst, Birgitte. / Translating biased signaling in the ghrelin receptor system into differential in vivo functions. I: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Bind 115, Nr. 43. s. E10255-E10264.

Bibtex

@article{e98f7574e3ce4ed6a796ea688aafa7f5,
title = "Translating biased signaling in the ghrelin receptor system into differential in vivo functions",
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.",
author = "Franziska Mende and Cecilie Hundahl and Bianca Plouffe and Skov, {Louise Julie} and Bj{\o}rn Sivertsen and Madsen, {Andreas Nygaard} and Michael L{\"u}ckmann and Diep, {Thi Ai} and Stefan Offermanns and Frimurer, {Thomas Michael} and Michel Bouvier and Birgitte Holst",
year = "2018",
doi = "10.1073/pnas.1804003115",
language = "English",
volume = "115",
pages = "E10255--E10264",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "43",

}

RIS

TY - JOUR

T1 - Translating biased signaling in the ghrelin receptor system into differential in vivo functions

AU - Mende, Franziska

AU - Hundahl, Cecilie

AU - Plouffe, Bianca

AU - Skov, Louise Julie

AU - Sivertsen, Bjørn

AU - Madsen, Andreas Nygaard

AU - Lückmann, Michael

AU - Diep, Thi Ai

AU - Offermanns, Stefan

AU - Frimurer, Thomas Michael

AU - Bouvier, Michel

AU - Holst, Birgitte

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1804003115

DO - 10.1073/pnas.1804003115

M3 - Journal article

C2 - 30301804

VL - 115

SP - E10255-E10264

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 43

ER -

ID: 209112490