Analysis of the Function of Receptor Oligomers by Operational Models of Agonism

Evidences from different techniques suggest that GPCRs oligomerize into homo- and hetero-oligomers. Oligomerization adds an extra level of complexity to receptor functionality because the allosteric interactions between protomers modify the intrinsic functional capacity of the single protomers. Reliable mathematical models are needed to quantify and mechanistically explain the observed functional effects. The operational model of agonism of Black and Leff (1983) constitutes a cornerstone in the description of agonism by providing parameter estimates for the pharmacological properties of affinity and efficacy. In the present study we revisit the operational model of agonism through the description of various adaptations and extensions to the model developed in our group. In particular, models for homo- and heterodimer receptors are discussed. Inclusion in the models of constitutive receptor activity and explicit parameters for cooperativity are useful for the interpretation of experimental data. Moreover, these quantitative approaches may clarify complex experimental relationships related to biased signaling. Finally, it is expected that the combined application of mathematical modeling and structural techniques will represent a powerful strategy to identify, visualize and quantify the allosteric interactions responsible for the observed functional effects dependent on receptor aggregation. This information is fundamental in the design and development of drug discovery programs. We believe that further efforts in this field are necessary for the construction of a robust and flexible modern pharmacology.