ArticleBritish journal of pharmacology2012
Development of operational models of receptor activation including constitutive receptor activity and their use to determine the efficacy of the chemokine CCL17 at the CC chemokine receptor CCR4.
Article in British journal of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Skipping a pillar does not make for strong foundations: Pharmacokinetic-pharmacodynamic reasoning behind the shape of dose-response relationships in oncology.CPT: pharmacometrics & systems pharmacology · 2023Pooled it
- CCR-CCL axes as key upstream influencers of pancreatic ductal adenocarcinoma: CCR2-CCL2, CCR5-CCL5, CCR4-CCL17/22, CCR6-CCL20, CCR7-CCL19/21.Frontiers in immunology · 2026Review
- AMolecular pharmacology · 2023Article
- Quantitative receptor model for responses that are left- or right-shifted versus occupancy (are more or less concentration sensitive): the SABRE approach.Frontiers in pharmacology · 2023Article
- Phosphoproteomic mapping of CCR5 and ACKR2 signaling properties.Frontiers in molecular biosciences · 2022Article
- Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10.International journal of molecular sciences · 2021Article
- A single unified model for fitting simple to complex receptor response data.Scientific reports · 2020Article
- Analyzing kinetic signaling data for G-protein-coupled receptors.Scientific reports · 2020Article
- Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.Neuropharmacology · 2019Article
- A Receptor Model With Binding Affinity, Activation Efficacy, and Signal Amplification Parameters for Complex Fractional Response Versus Occupancy Data.Frontiers in pharmacology · 2019Article
- Differential expression of functional chemokine receptors on human blood and lung group 2 innate lymphoid cells.The Journal of allergy and clinical immunology · 2019Article
- A method for the quantification of biased signalling at constitutively active receptors.British journal of pharmacology · 2018Article
- An evaluation of the operational model when applied to quantify functional selectivity.British journal of pharmacology · 2018Article
- Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor.Journal of theoretical biology · 2018Article
- A three-parameter two-state model of receptor function that incorporates affinity, efficacy, and signal amplification.Pharmacology research & perspectives · 2017Article
- Pharmacological properties of acid N-thiazolylamide FFA2 agonists.Pharmacology research & perspectives · 2015Article
- Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists.European journal of pharmacology · 2014Article
- Antagonism of human CC-chemokine receptor 4 can be achieved through three distinct binding sites on the receptor.Pharmacology research & perspectives · 2013Article
- The chemokine receptor CCR1 is constitutively active, which leads to G protein-independent, β-arrestin-mediated internalization.The Journal of biological chemistry · 2013Article
- Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models.British journal of pharmacology · 2013Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND PURPOSE The operational model provides a key conceptual framework for the analysis of pharmacological data. However, this model does not include constitutive receptor activity, a frequent phenomenon in modern pharmacology, particularly in recombinant systems. Here, we developed extensions of the operational model which include constitutive activity and applied them to effects of agonists at the chemokine receptor CCR4. EXPERIMENTAL APPROACH The effects of agonists of CCR4 on [(35) S]GTPγS binding to recombinant cell membranes and on the filamentous (F-) actin content of human CD4(+) CCR4(+) T cells were determined. The basal [(35) S]GTPγS binding was changed by varying the GDP concentration whilst the basal F-actin contents of the higher expressing T cell populations were elevated, suggesting constitutive activity of CCR4. Both sets of data were analysed using the mathematical models. RESULTS The affinity of CCL17 (also known as TARC) derived from analysis of the T cell data (pK(a) = 9.61 ± 0.17) was consistent with radioligand binding experiments (9.50 ± 0.11) while that from the [(35) S]GTPγS binding experiments was lower (8.27 ± 0.09). Its intrinsic efficacy differed between the two systems (110 in T cells vs. 11). CONCLUSIONS AND IMPLICATIONS The presence of constitutive receptor activity allows the absolute intrinsic efficacy of agonists to be determined without a contribution from the signal transduction system. Intrinsic efficacy estimated in this way is consistent with Furchgott's definition of this property. CCL17 may have a higher intrinsic efficacy at CCR4 in human T cells than that expressed recombinantly in CHO cells.
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