A method for the quantification of biased signalling at constitutively active receptors

British Journal of Pharmacology
David A Hall, J Giraldo

Abstract

Biased agonism, the ability of an agonist to differentially activate one of several signal transduction pathways when acting at a given receptor, is an increasingly recognized phenomenon at many receptors. The Black and Leff operational model lacks a way to describe constitutive receptor activity and hence inverse agonism. Thus, it is impossible to analyse the biased signalling of inverse agonists using this model. In this theoretical work, we develop and illustrate methods for the analysis of biased inverse agonism. Methods were derived for quantifying biased signalling in systems that demonstrate constitutive activity using the modified operational model proposed by Slack and Hall. The methods were illustrated using Monte Carlo simulations. The Monte Carlo simulations demonstrated that, with an appropriate experimental design, the model parameters are 'identifiable'. The method is consistent with methods based on the measurement of intrinsic relative activity (RAi ) (ΔΔlogR or ΔΔlog(τ/Ka )) proposed by Ehlert and Kenakin and their co-workers but has some advantages. In particular, it allows the quantification of ligand bias independently of 'system bias' removing the requirement to normalize to a standard ligand. In systems w...Continue Reading

References

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Aug 4, 2012·ACS Chemical Neuroscience·Terry KenakinSteven Novick
Jan 10, 2013·The Journal of Pharmacology and Experimental Therapeutics·Scott M DeWireJonathan D Violin
Feb 16, 2013·Nature Reviews. Drug Discovery·Terry Kenakin, Arthur Christopoulos
Feb 19, 2013·Progress in Molecular Biology and Translational Science·David A Hall
Oct 30, 2014·Journal of Receptor and Signal Transduction Research·Richard S L Stein, Frederick J Ehlert
Jul 1, 2015·Trends in Pharmacological Sciences·Frederick J Ehlert
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Aug 18, 2016·Nature·Aashish ManglikBrian K Shoichet
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Oct 22, 2017·British Journal of Pharmacology·Stephen Ph AlexanderUNKNOWN CGTP Collaborators
Nov 15, 2017·Scientific Reports·Javier BurgueñoJesús Giraldo

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Citations

Jan 25, 2020·British Journal of Pharmacology·David B FinlayMichelle Glass
Mar 14, 2019·Biomolecular Concepts·Rafael FrancoGemma Navarro
Jul 30, 2019·Journal of Theoretical Biology·Terry Kenakin
Dec 29, 2020·Frontiers in Immunology·Beom K Choi, Hyeon-Woo Lee
Jan 16, 2021·Journal of Chemical Information and Modeling·Adrián RicarteJesús Giraldo

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