Extensions of receptor theory to include dimerised and dimerising receptor dynamics #

Lloyd Bridge, Carla White

14:50 Monday in 2Q50/51.

Part of the Mathematical pharmacology session.

Abstract #

Classical receptor theory in pharmacological analysis considers schematics comprising ligands binding monomeric (single) receptors. Extension of the theory beyond such schematics is required for the increasingly recognised possibility of pre-dimerised receptors (eg., constitutively formed G protein-coupled receptor dimers) and higher-order oligomers. Understanding the quantitative and qualitative role of binding cooperativity factors across a dimerised receptor is an essential first step towards answering questions regarding the diversity of potential binding profiles and downstream signalling responses. Here we extend the theory by way of formulation and analysis of differential equation models for the dynamics of single-ligand and two-ligand binding at dimerised receptor and dimerising receptors. In addition to the new insights gained from this analysis, we present new results from structural identifiability analysis (SIA) of the models; parameter estimation is a key endeavour in biological data fitting, and establishing the theoretical identifiability properties of the models is an important, and often overlooked, step of the analysis.