ArticleThe Journal of biological chemistry2015
Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 98 citations in OpenAlex.
- LEAP2 as a therapeutic target in obesity and cardiometabolic disorders.Reviews in endocrine & metabolic disorders · 2026Review
- Membrane cholesterol modulates engagement of β-arrestin with the ghrelin receptor.Communications biology · 2026Article
- Inhibition of constitutive activity of the atypical chemokine receptor 3 by the small-molecule inverse agonist VUF16840.Molecular pharmacology · 2025Article
- The Art of Chilling Out: How Neurons Regulate Torpor.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Hunger signalling in the olfactory bulb primes exploration, food-seeking and peripheral metabolism.Molecular metabolism · 2024Article
- Ghrelin receptor signaling in health and disease: a biased view.Trends in endocrinology and metabolism: TEM · 2023Review
- Platelet P2YBMC biology · 2023Article
- Establishment of a Cell Line Stably Expressing the Growth Hormone Secretagogue Receptor to Identify Crocin as a Ghrelin Agonist.Biomolecules · 2022Article
- Review
- GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner.Cellular and molecular life sciences : CMLS · 2022Article
- Discovery of a functionally selective ghrelin receptor (GHSRProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor.Journal of medicinal chemistry · 2022Review
- The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions.International journal of molecular sciences · 2022Review
- Targeting the Ghrelin Receptor as a Novel Therapeutic Option for Epilepsy.Biomedicines · 2021Review
- Concerted conformational dynamics and water movements in the ghrelin G protein-coupled receptor.eLife · 2021Article
- Ghrelin octanoylation by ghrelinOpen biology · 2021Review
- Allosteric modulation of ghrelin receptor signaling by lipids.Nature communications · 2021Article
- Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats.International journal of molecular sciences · 2021Article
- LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling.Frontiers in pharmacology · 2021Article
- Biased Ghrelin Receptor Signaling and the Dopaminergic System as Potential Targets for Metabolic and Psychological Symptoms of Anorexia Nervosa.Frontiers in endocrinology · 2021Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The G protein-coupled receptor GHS-R1a mediates ghrelin-induced growth hormone secretion, food intake, and reward-seeking behaviors. GHS-R1a signals through Gq, Gi/o, G13, and arrestin. Biasing GHS-R1a signaling with specific ligands may lead to the development of more selective drugs to treat obesity or addiction with minimal side effects. To delineate ligand selectivity at GHS-R1a signaling, we analyzed in detail the efficacy of a panel of synthetic ligands activating the different pathways associated with GHS-R1a in HEK293T cells. Besides β-arrestin2 recruitment and ERK1/2 phosphorylation, we monitored activation of a large panel of G protein subtypes using a bioluminescence resonance energy transfer-based assay with G protein-activation biosensors. We first found that unlike full agonists, Gq partial agonists were unable to trigger β-arrestin2 recruitment and ERK1/2 phosphorylation. Using G protein-activation biosensors, we then demonstrated that ghrelin promoted activation of Gq, Gi1, Gi2, Gi3, Goa, Gob, and G13 but not Gs and G12. Besides, we identified some GHS-R1a ligands that preferentially activated Gq and antagonized ghrelin-mediated Gi/Go activation. Finally, we unambiguously demonstrated that in addition to Gq, GHS-R1a also promoted constitutive activation of G13. Importantly, we identified some ligands that were selective inverse agonists toward Gq but not of G13. This demonstrates that bias at GHS-R1a signaling can occur not only with regard to agonism but also to inverse agonism. Our data, combined with other in vivo studies, may facilitate the design of drugs selectively targeting individual signaling pathways to treat only the therapeutically relevant function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.