Seminar by Dr. Jesús Giraldo

Universitat Autònoma de Barcelona (Spain)

Quantifying GPCR Signaling in an Oligomeric Context: Exploring Therapeutic Opportunities

Evidences from different techniques suggest that G protein-coupled receptors (GPCRs) oligomerize into homo- and hetero-oligomers. Oligomerization adds an extra level of complexity to receptor function because the allosteric interactions between protomers modify the intrinsic functional capacity of the single protomers [1]. Reliable mathematical models are needed to quantify and mechanistically explain the observed functional effects [2]. In this talk, a mathematical model for GPCR heterodimerization will be shown. 

First, I will consider that the heterodimeric system is in equilibrium. Ligand-receptor binding and receptor function will be quantified in terms of equilibrium dissociation constants and functional parameters accounting for receptor activation and the final observed effect [3]. Typical quantities such as binding and functional cooperativities, receptor constitutive activity and inverse and biased agonism will be examined through concentration-effects curves resulting from the parameters of the mathematical model [3].

Second, binding kinetics will be included. Binding kinetics and, consequently, the time factor are conceptual pieces in the mechanism of drug action that should not be neglected in pharmacological research and pharmaceutical development. The mathematical model developed in [3] for a receptor heterodimer will be adapted by replacing equilibrium dissociation constants with rate constants. This will allow us to find a mathematical relationship that links the cooperativity rate constant parameters between the different species of the heterodimeric receptor. This relationship can lead to a variety of kinetic results for a single binding cooperativity value obtained in an equilibrium experiment [4]. The ordinary differential equations (ODEs) for the binding kinetics included in receptor heterodimerization have been solved and the time-dependent concentration of the different receptor species will be shown under different conditions (excess of ligand concentration or not) of the ligands involved in the system.

In order to gain structural insight into the dimerization process, we have performed coarse-grained molecular dynamics simulations of the self-assembly of a GPCR heterodimer. As a case study, we investigated the dimer formed by the mu-opioid and the cannabinoid CB1 receptors. This set the basis for future structural analysis of drug cooperativity effects.

Mathematical and structural simulations are complementary to each other and may provide a conceptual framework for mechanism-based drug combination therapies in the context of receptor heteromerization.

References

1          Christopoulos, A. and Kenakin, T. (2002) G protein-coupled receptor allosterism and complexing. Pharmacol Rev 54, 323-374

2          Giraldo, J. et al. (2022) Analysis of the Function of Receptor Oligomers by Operational Models of Agonism. In Comprehensive Pharmacology. (Vol. 1) (Kenakin, T.E., ed.), pp. 337-359, Elsevier

3          Zhou, B. and Giraldo, J. (2018) Quantifying the allosteric interactions within a G-protein-coupled receptor heterodimer. Drug Discov. Today 23 (1), 7-11

4          Díaz, Ó. et al. (2022) Allosteric binding cooperativity in a kinetic context. Drug Discov Today, 103441