Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor.
Journal of theoretical biology
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Bridge, L., Mead, J., Frattini, E., Winfield, I., & Ladds, G. (2018). Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor.. Journal of theoretical biology, 442 44-65. https://doi.org/10.1016/j.jtbi.2018.01.010
Theoretical models of G protein-coupled receptor (GPCR) concentration-response relationships often assume an agonist producing a single functional response via a single active state of the recep- tor. These models have largely been analysed assuming steady-state conditions. There is now much experimental evidence to suggest that many GPCRs can exist in multiple receptor conformations and elicit numerous functional responses, with ligands having the potential to activate different sig- nalling pathways to varying extents - a concept referred to as biased agonism, functional selectivity or pluri-dimensional efficacy. Moreover, recent experimental results indicate a clear possibility for time-dependent bias, whereby an agonist’s bias with respect to different pathways may vary dy- namically. Efforts towards understanding the implications of temporal bias by characterising and quantifying ligand effects on multiple pathways will clearly be aided by extending current equi- librium binding and biased activation models to include G protein activation dynamics. Here, we present a new model of time-dependent biased agonism, based on ordinary differential equations for multiple cubic ternary complex activation models with G protein cycle dynamics. This model allows simulation and analysis of multi-pathway activation bias dynamics at a single receptor for the first time, at the level of active G protein (αGT P ), towards the analysis of dynamic functional responses. The model is generally applicable to systems with NG G proteins and N∗ active recep- tor states. Numerical simulations for NG = N∗ = 2 reveal new insights into the effects of system parameters (including cooperativities, and ligand and receptor concentrations) on bias dynamics, highlighting new phenomena including the dynamic inter-conversion of bias direction. Further, we fit this model to ‘wet’ experimental data for two competing G proteins (Gi and Gs) that become activated upon stimulation of the adenosine A1 receptor with adenosine derivative compounds. Fi- nally, we show that our model can qualitatively describe the temporal dynamics of this competing G protein activation.
Animals, Humans, GTP-Binding Proteins, Receptors, G-Protein-Coupled, Ligands, Signal Transduction, Algorithms, Models, Biological
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External DOI: https://doi.org/10.1016/j.jtbi.2018.01.010
This record's URL: https://www.repository.cam.ac.uk/handle/1810/274028