ArticleThe Journal of biological chemistry2012
Modulation of constitutive activity and signaling bias of the ghrelin receptor by conformational constraint in the second extracellular loop.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 38 citations in OpenAlex.
- A Dimer for Dinner: The Impact of GHS-R1a Heterodimerization on Feeding Circuits.Biomolecules · 2026Review
- GPCR Biased Signaling in Metabolism.Handbook of experimental pharmacology · 2026Review
- Initial Pharmacological Characterization of a Major Hydroxy Metabolite of PF-5190457: Inverse Agonist Activity of PF-6870961 at the Ghrelin Receptor.The Journal of pharmacology and experimental therapeutics · 2023Article
- Ghrelin receptor signaling in health and disease: a biased view.Trends in endocrinology and metabolism: TEM · 2023Review
- Chemogenetics of cell surface receptors: beyond genetic and pharmacological approaches.RSC chemical biology · 2022Review
- Discovery of a functionally selective ghrelin receptor (GHSRProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Functional characterization of naturally-occurring constitutively activating/inactivating mutations in equine follicle-stimulating hormone receptor.Animal bioscience · 2022Article
- Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor.Nature communications · 2021Article
- In silico strategy for detailing the binding modes of a novel family of peptides proven as ghrelin receptor agonists.Journal of molecular modeling · 2020Article
- Metabolic insights from a GHSR-A203E mutant mouse model.Molecular metabolism · 2020Article
- Advances in therapeutic peptides targeting G protein-coupled receptors.Nature reviews. Drug discovery · 2020Review
- Structural Model of Ghrelin Bound to its G Protein-Coupled Receptor.Structure (London, England : 1993) · 2019Article
- Translating biased signaling in the ghrelin receptor system into differential in vivo functions.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The C-terminal Phosphorylation Sites of eel Follicle-Stimulating Hormone Receptor are Important Role in the Signal Transduction.Development & reproduction · 2018Article
- G Protein-coupled Receptor Biased Agonism.Journal of cardiovascular pharmacology · 2016Review
- Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor:Gq complex.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Structural basis for constitutive activity and agonist-induced activation of the enteroendocrine fat sensor GPR119.British journal of pharmacology · 2014Article
- G Protein and β-arrestin signaling bias at the ghrelin receptor.The Journal of biological chemistry · 2014Article
- The growth hormone secretagogue receptor: its intracellular signaling and regulation.International journal of molecular sciences · 2014Review
- Functionally biased signalling properties of 7TM receptors - opportunities for drug development for the ghrelin receptor.British journal of pharmacology · 2013Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Based on a rare, natural Glu for Ala-204(C+6) variant located six residues after the conserved Cys residue in extracellular loop 2b (ECL2b) associated with selective elimination of the high constitutive signaling of the ghrelin receptor, this loop was subjected to a detailed structure functional analysis. Introduction of Glu in different positions demonstrated that although the constitutive signaling was partly reduced when introduced in position 205(C+7) it was only totally eliminated in position 204(C+6). No charge-charge interaction partner could be identified for the Glu(C+6) variant despite mutational analysis of a number of potential partners in the extracellular loops and outer parts of the transmembrane segments. Systematic probing of position 204(C+6) with amino acid residues of different physicochemical properties indicated that a positively charged Lys surprisingly provided phenotypes similar to those of the negatively charged Glu residue. Computational chemistry analysis indicated that the propensity for the C-terminal segment of extracellular loop 2b to form an extended α-helix was increased from 15% in the wild type to 89 and 82% by introduction in position 204(C+6) of a Glu or a Lys residue, respectively. Moreover, the constitutive activity of the receptor was inhibited by Zn(2+) binding in an engineered metal ion site, stabilizing an α-helical conformation of this loop segment. It is concluded that the high constitutive activity of the ghrelin receptor is dependent upon flexibility in the C-terminal segment of extracellular loop 2 and that mutations or ligand binding that constrains this segment and thereby conceivably the movements of transmembrane domain V relative to transmembrane domain III inhibits the high constitutive signaling.
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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.