G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

Evron, Tama; Peterson, Sean M.; Urs, Nikhil M.; Bai, Yushi; Rochelle, Lauren K.; Caron, Marc G.; Barak, Larry S.

doi:10.1074/jbc.m114.581397

Cited by 63 publications

(81 citation statements)

References 71 publications

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“…Previous work in cellular systems supported a critical role for the GHSR C-terminal domain in receptor trafficking (18,19). Here, several lines of evidence support the notion that the distal part of the C-terminal tail of GHSR inhibits GHSR function.…”

Section: Discussionsupporting

confidence: 78%

“…This hypothesis is supported by another mutant GHSR (GHSR-P148A), which cannot interact with β-arrestin 2 but is still internalized in response to agonist stimulation, and shows increased agonist-induced G protein-dependent signaling (19). In the absence of ligand, however, the wild-type GHSR and GHSR-Q343X isoforms showed similar basal MAPK-and RhoA-dependent signaling, indicating that the Q343X mutation does not modify constitutive signaling.…”

Section: Discussionmentioning

confidence: 94%

“…The C terminus determines trafficking patterns and interaction with β-arrestin 2 presumably in a phosphorylation-dependent manner (18,19). The Q343X mutation also increased agonist-induced Ca 2+ mobilization through the G αq/11 -PLC pathway and SRE responses through the MAPK and RhoA pathways.…”

Section: Discussionmentioning

confidence: 99%

“…β-arrestin 2 recruitment by GHSR requires the C-terminal tail, and presumably the phosphorylation patterns of Ser and Thr residues in this domain (18,19). Because most putative S/T phosphorylation sites in the C terminus are missing in the Q343X mutant, it seemed likely that -arrestin recruitment to the mutant receptor would be impaired.…”

Section: The Q343x Mutation In Ghsr Impairs Ligand-induced Internalizmentioning

confidence: 99%

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Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

et al. 2016

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The ability of the gut hormone ghrelin to promote positive energy balance is mediated by the growth hormone secretagogue receptor (GHSR). GHSR is a G protein-coupled receptor (GPCR) that is found centrally and peripherally and that can signal in a ligand-independent manner basally or when heterodimerized with other GPCRs. However, current Ghsr knockout models cannot dissect ghrelindependent and -independent signaling, precluding assessment of the physiological importance of these signaling pathways. An animal model carrying a Ghsr mutation that preserves GHSR cell surface abundance, but selectively alters GHSR signaling, would be a useful tool to decipher GHSR signaling in vivo. We used rats with the Ghsr Q343X mutation (Ghsr M/M ), which is predicted to delete the distal part of the GHSR C-terminus tail, a domain critical for the signal termination processes of receptor internalization and -arrestin recruitment. In cells, the Q343X GHSR mutant showed enhanced ligandinduced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination. Ghsr M/M rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover, Ghsr M/M rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions, Ghsr M/M rats showed increased body weight, adiposity and reduced glucose tolerance. Overall, our data stresses the physiological role of the distal domain of GHSR C-terminus as a suppressor of ghrelin sensitivity and we propose using the Ghsr M/M rat as a physiological model of gain-of-function in Ghsr to identify treatments for obesity-related conditions.3

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: The Q343x Mutation In Ghsr Impairs Ligand-induced Internalizmentioning

confidence: 99%

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Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

et al. 2016

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“…1 and 2, A and B). Because it was reported that GHS-R1a activated ERK1/2 through G q/11 , G i , and arrestin-dependent pathways (28,43,44), we tested the efficacy of our ligands toward ERK1/2 activation. All compounds displayed comparable efficacy to promote ␤-arrestin2 recruitment (Table 2 and Fig.…”

Section: Efficacy Of Ghs-r1a Ligands Toward ␤-Arrestin2mentioning

confidence: 99%

Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling

M’Kadmi

Leyris

Onfroy

et al. 2015

Journal of Biological Chemistry

107

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Background: GHS-R1a activates multiple signaling pathways mediating feeding and addictive behaviors. Results: Some GHS-R1a ligands activate G q but not G i/o and fail to recruit ␤-arrestin2; others act as selective inverse agonists at G q compared with G 13 . Conclusion: Synthetic ligands can selectively activate or reverse G q -dependent signaling at GHS-R1a. Significance: Ligand-biased signaling can be exploited for the development of selective drugs to treat GHS-R1a-mediated disorders.

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GPCR Signaling from Intracellular Membranes

Jong¹,

Harmon²,

O’Malley³

2022

GPCRs as Therapeutic Targets

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G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

Cited by 63 publications

References 71 publications

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling

GPCR Signaling from Intracellular Membranes

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G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

Cited by 63 publications

References 71 publications

Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling

GPCR Signaling from Intracellular Membranes

Contact Info

Product

Resources

About

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite