ArticleThe Journal of biological chemistry2014
G Protein and β-arrestin signaling bias at the ghrelin receptor.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 75 citations in OpenAlex.
- The Orally Available Ghrelin Receptor-Agonist AC01 Improves Systolic Function in HFrEF Mice and Nonhuman Primates.JACC. Basic to translational science · 2026Article
- Syndecans modulate ghrelin receptor signaling.Journal of molecular endocrinology · 2025Article
- An atomic look at the interface of GHSR and its partners.Computational and structural biotechnology journal · 2024Article
- Ghrelin receptor signaling in health and disease: a biased view.Trends in endocrinology and metabolism: TEM · 2023Review
- Allosteric crosstalk in modular proteins: Function fine-tuning and drug design.Computational and structural biotechnology journal · 2023Review
- Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways.Acta pharmacologica Sinica · 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
- Molecular mechanism of agonism and inverse agonism in ghrelin receptor.Nature communications · 2022Article
- Targeting the Ghrelin Receptor as a Novel Therapeutic Option for Epilepsy.Biomedicines · 2021Review
- Selectively increasing GHS-R1a expression in dCA1 excitatory/inhibitory neurons have opposite effects on memory encoding.Molecular brain · 2021Article
- Relationship between Orexigenic Peptide Ghrelin Signal, Gender Difference and Disease.International journal of molecular sciences · 2021Review
- Review
- Biased signaling in naturally occurring mutations of G protein-coupled receptors associated with diverse human diseases.Biochimica et biophysica acta. Molecular basis of disease · 2021Review
- β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.Cell · 2020Article
- The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a.Science signaling · 2020Article
- Integration of Cell-Free Expression and Solid-State NMR to Investigate the Dynamic Properties of Different Sites of the Growth Hormone Secretagogue Receptor.Frontiers in pharmacology · 2020Article
- Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs.ACS pharmacology & translational science · 2019Article
- Differential Effects of a Full and Biased Ghrelin Receptor Agonist in a Mouse Kindling Model.International journal of molecular sciences · 2019Article
- The Role of Ghrelin in Regulating Synaptic Function and Plasticity of Feeding-Associated Circuits.Frontiers in cellular neuroscience · 2019Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The G protein-coupled ghrelin receptor GHSR1a is a potential pharmacological target for treating obesity and addiction because of the critical role ghrelin plays in energy homeostasis and dopamine-dependent reward. GHSR1a enhances growth hormone release, appetite, and dopamine signaling through G(q/11), G(i/o), and G(12/13) as well as β-arrestin-based scaffolds. However, the contribution of individual G protein and β-arrestin pathways to the diverse physiological responses mediated by ghrelin remains unknown. To characterize whether a signaling bias occurs for GHSR1a, we investigated ghrelin signaling in a number of cell-based assays, including Ca(2+) mobilization, serum response factor response element, stress fiber formation, ERK1/2 phosphorylation, and β-arrestin translocation, utilizing intracellular second loop and C-tail mutants of GHSR1a. We observed that GHSR1a and β-arrestin rapidly form metastable plasma membrane complexes following exposure to an agonist, but replacement of the GHSR1a C-tail by the tail of the vasopressin 2 receptor greatly stabilizes them, producing complexes observable on the plasma membrane and also in endocytic vesicles. Mutations of the contiguous conserved amino acids Pro-148 and Leu-149 in the GHSR1a intracellular second loop generate receptors with a strong bias to G protein and β-arrestin, respectively, supporting a role for conformation-dependent signaling bias in the wild-type receptor. Our results demonstrate more balance in GHSR1a-mediated ERK signaling from G proteins and β-arrestin but uncover an important role for β-arrestin in RhoA activation and stress fiber formation. These findings suggest an avenue for modulating drug abuse-associated changes in synaptic plasticity via GHSR1a and indicate the development of GHSR1a-biased ligands as a promising strategy for selectively targeting downstream signaling events.
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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.