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.

British Journal of Pharmacology
R J Slack, D A Hall

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 v...Continue Reading

References

Oct 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·T Costa, A Herz
Oct 1, 1985·Analytical Biochemistry·P K SmithD C Klenk
Dec 22, 1983·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·J W Black, P Leff
Jan 27, 1998·The Journal of Biological Chemistry·T ImaiP W Gray
Dec 21, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·D P AndrewL Wu
Nov 27, 2002·European Journal of Pharmacology·Yuntao WanShelby P Umland
Dec 6, 2003·Pharmacological Reviews·Richard R NeubigUNKNOWN International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification
Jun 29, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jonathan D UrbanRichard B Mailman
Nov 9, 2011·British Journal of Pharmacology·Stephen P H AlexanderJohn A Peters

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Citations

Jan 10, 2013·BMC Pharmacology & Toxicology·Niels Bindslev
May 1, 2015·Expert Opinion on Drug Discovery·Rumin Zhang, Michael Kavana
Dec 17, 2014·Pharmacology Research & Perspectives·Robert J SlackDavid A Hall
Aug 4, 2015·Pharmacology Research & Perspectives·Andrew J BrownSimon J Dowell
Feb 20, 2018·British Journal of Pharmacology·Xiao ZhuStephen B Duffull
Mar 3, 2018·British Journal of Pharmacology·David A Hall, Jesús Giraldo
Jul 25, 2020·Scientific Reports·Sam R J HoareLloyd J Bridge
May 1, 2021·International Journal of Molecular Sciences·Herman D LimMartin J Stone

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