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Mathematical modelling of signalling in a two-ligand G-protein coupled receptor system: Agonist-antagonist competition

Bridge, Lloyd; King, J. R.; Hill, S. J.; Owen, M. R.

Authors

Lloyd Bridge Lloyd.Bridge@uwe.ac.uk
Senior Lecturer in Mathematics

J. R. King

S. J. Hill

M. R. Owen



Abstract

A new mathematical model of cell signalling for a two-ligand G-protein coupled receptor (GPCR) system is presented. This model extends the single-ligand cubic ternary complex to account for the possibility of an agonist and an antagonist competing for receptor sites. The G-protein cycle is included, and signalling as far as the dissociated Gα subunit is considered. Numerical simulations are performed, and the effects on the system dynamics, such as peak and plateau behaviour, of antagonist "stickiness", and of the doses of agonist and antagonist, are discussed. Under certain parameter regimes, the plateau response is subject to surmountable antagonism, while the peak response is subject to insurmountable antagonism. The numerical results reveal responses evolving over a number of time-scales. An asymptotic analysis is presented which identifies dominant reactions and gives leading order solutions over these various time-scales, for a number of parameter regimes. © 2009 Elsevier Inc. All rights reserved.

Journal Article Type Article
Acceptance Date Nov 16, 2009
Publication Date Feb 1, 2010
Journal Mathematical Biosciences
Print ISSN 0025-5564
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 223
Issue 2
Pages 115-132
DOI https://doi.org/10.1016/j.mbs.2009.11.005
Keywords g-protein coupled receptors, agonist–antagonist competition, cell signalling, asymptotic analysis
Public URL https://uwe-repository.worktribe.com/output/983725
Publisher URL http://dx.doi.org/10.1016/j.mbs.2009.11.005