The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a

Alix A J Rouault; Luciana K Rosselli-Murai; Ciria C Hernandez; Luis E Gimenez; Gregory G Tall; Julien A Sebag

doi:10.1126/scisignal.aax4569

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The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a

Journal article

Open access

Peer reviewed

The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a

Alix A J Rouault, Luciana K Rosselli-Murai, Ciria C Hernandez, Luis E Gimenez, Gregory G Tall and Julien A Sebag

Science signaling, Vol.13(613), p.eaax4569

01/07/2020

DOI: 10.1126/scisignal.aax4569

PMCID: PMC7291826

PMID: 31911434

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Abstract

Ghrelin is a hormone secreted by the stomach during fasting periods and acts through its receptor, the growth hormone secretagogue 1a (GHSR1a), to promote food intake and prevent hypoglycemia. As such, GHSR1a is an important regulator of energy and glucose homeostasis and a target for the treatment of obesity. Here, we showed that the accessory protein MRAP2 altered GHSR1a signaling by inhibiting its constitutive activity, as well as by enhancing its G protein-dependent signaling and blocking the recruitment and signaling of β-arrestin in response to ghrelin. In addition, the effects of MRAP2 on the Gα\nand β-arrestin pathways were independent and involved distinct regions of MRAP2. These findings may have implications for the regulation of ghrelin function in vivo and the role of MRAP2 in energy homeostasis. They also show that accessory proteins can bias signaling downstream of GPCRs in response to their endogenous agonist.

GTP-Binding Protein alpha Subunits, Gq-G11 - genetics

Animals

Cricetulus

Energy Metabolism

Signal Transduction

Humans

Adaptor Proteins, Signal Transducing - genetics

Adaptor Proteins, Signal Transducing - metabolism

GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism

Receptors, Ghrelin - immunology

Receptors, Ghrelin - genetics

CHO Cells

Details

Title: Subtitle: The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a
Creators: Alix A J Rouault - Department of Molecular Physiology and Biophysics, Fraternal Order of Eagles Diabetes Research Center, Iowa Neuroscience Institute, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA
Luciana K Rosselli-Murai - Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
Ciria C Hernandez - Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
Luis E Gimenez - Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
Gregory G Tall - Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
Julien A Sebag - Department of Molecular Physiology and Biophysics, Fraternal Order of Eagles Diabetes Research Center, Iowa Neuroscience Institute, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA. julien-sebag@uiowa.edu
Resource Type: Journal article
Publication Details: Science signaling, Vol.13(613), p.eaax4569
Publisher: United States
DOI: 10.1126/scisignal.aax4569
PMID: 31911434
PMCID: PMC7291826
ISSN: 1945-0877
eISSN: 1937-9145
Grant note: R01 GM088242 / NIGMS NIH HHS\nR01 GM120110 / NIGMS NIH HHS\nR01 DK115567 / NIDDK NIH HHS\nP30 DK054759 / NIDDK NIH HHS
Language: English
Date published: 01/07/2020
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984070249402771

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