ArticlePloS one2015
The extracellular loop 2 (ECL2) of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 15 papers.
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15 citing papers in PubMed, 35 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Activity-restoring mutations in the histamine HProtein science : a publication of the Protein Society · 2026Article
- Conserved residues in the extracellular loop 2 regulate Stachel-mediated activation of ADGRG2.Scientific reports · 2021Article
- Molecular Modeling of Histamine Receptors-Recent Advances in Drug Discovery.Molecules (Basel, Switzerland) · 2021Review
- A Dynamic, Split-Luciferase-Based Mini-G Protein Sensor to Functionally Characterize Ligands at All Four Histamine Receptor Subtypes.International journal of molecular sciences · 2020Article
- Benchmarking GPCR homology model template selection in combination with de novo loop generation.Journal of computer-aided molecular design · 2020Article
- Enigmatic Histamine Receptor HLife (Basel, Switzerland) · 2020Review
- Basal Histamine HChemistry (Weinheim an der Bergstrasse, Germany) · 2019Article
- Importance of the second extracellular loop for melatonin MTBritish journal of pharmacology · 2018Article
- Hybrid approach to structure modeling of the histamine H3 receptor: Multi-level assessment as a tool for model verification.PloS one · 2017Article
- Pharmacological Characterization of Human Histamine Receptors and Histamine Receptor Mutants in the Sf9 Cell Expression System.Handbook of experimental pharmacology · 2017Review
- Aryl-1,3,5-triazine ligands of histamine HInflammation research : official journal of the European Histamine Research Society ... [et al.] · 2017Article
- The Activation Pathway of Human Rhodopsin in Comparison to Bovine Rhodopsin.The Journal of biological chemistry · 2015Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In contrast to the corresponding mouse and rat orthologs, the human histamine H4 receptor (hH4R) shows extraordinarily high constitutive activity. In the extracellular loop (ECL), replacement of F169 by V as in the mouse H4R significantly reduced constitutive activity. Stabilization of the inactive state was even more pronounced for a double mutant, in which, in addition to F169V, S179 in the ligand binding site was replaced by M. To study the role of the FF motif in ECL2, we generated the hH4R-F168A mutant. The receptor was co-expressed in Sf9 insect cells with the G-protein subunits Gαi2 and Gβ1γ2, and the membranes were studied in [3H]histamine binding and functional [35S]GTPγS assays. The potency of various ligands at the hH4R-F168A mutant decreased compared to the wild-type hH4R, for example by 30- and more than 100-fold in case of the H4R agonist UR-PI376 and histamine, respectively. The high constitutive activity of the hH4R was completely lost in the hH4R-F168A mutant, as reflected by neutral antagonism of thioperamide, a full inverse agonist at the wild-type hH4R. By analogy, JNJ7777120 was a partial inverse agonist at the hH4R, but a partial agonist at the hH4R-F168A mutant, again demonstrating the decrease in constitutive activity due to F168A mutation. Thus, F168 was proven to play a key role not only in ligand binding and potency, but also in the high constitutive activity of the hH4R.
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