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

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 ?-arrestin in response to ghrelin. In addition, the effects of MRAP2 on the G?q and ?-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.

SUBMITTER: Rouault AAJ

PROVIDER: S-EPMC7291826 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Rouault Alix A J AAJ Rosselli-Murai Luciana K LK Hernandez Ciria C CC Gimenez Luis E LE Tall Gregory G GG Sebag Julien A JA

Science signaling 20200107 613

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 th ...[more]

PMID: 31911434

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Project description:The aim of the present study was to identify the signaling mechanism(s) responsible for the modulation of growth hormone secretagogue receptor type 1a (GHSR1a)-associated Akt activity. Ghrelin leads to the activation of Akt through the interplay of distinct signaling mechanisms: an early G(i/o) protein-dependent pathway and a late pathway mediated by ?-arrestins. We found that the Src homology 2-containing protein tyrosine phosphatase (SHP-1) was an essential molecule in both G(i/o) protein-dependent and ?-arrestin-mediated pathways. More specifically, the role of SHP-1 in the G(i/o) protein-dependent pathway was demonstrated by the fact that the overexpression of a catalytically defective SHP-1 augments tyrosine phosphorylation of the PI3K regulatory subunit p85, leading to an increase in the phosphorylation of cSrc and phosphoinositide-dependent protein kinase 1, and finally activating Akt. The presence of SHP-1 in the ?-arrestin-scaffolded complex and its attenuating effect on the cSrc and Akt activities verified that SHP-1 regulates not only the G(i/o) protein-dependent pathway but also the ?-arrestin-mediated pathway. Assays performed in preadipocyte and adipocyte 3T3-L1 cells showed SHP-1 expression. According to our results in HEK-GHSR1a cells, ghrelin stimulated SHP-1 phosphorylation in 3T3-L1 cells. The increase in ghrelin-induced Akt activity was enhanced by small interfering RNA of SHP-1 in preadipocyte 3T3-L1 cells. These results were reproduced in white adipose tissue obtained from mice, in which SHP-1 exhibited higher expression in omental than in subcutaneous tissue. Furthermore, this pattern of expression was inverted in mice fed a high-fat diet, suggesting a role for SHP-1 in controlling ghrelin sensitivity in adipose tissue. Indeed, SHP-1 deficiency was associated with augmented ghrelin-evoked Akt phosphorylation in omental tissue, as well as decreased phosphorylation under overexpression of SHP-1 in subcutaneous tissue. These findings showed a novel role for SHP-1 in the regulation of Akt activity through the modulation of the ghrelin/GHSR1a system signaling.

Dataset Information

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

Publications

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

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