Application of Receptor Theory to Allosteric Modulation of Receptors

In this chapter, three topics are considered. The allosteric two-state model (ATSM) is compared with explicit multiconformational models. This demonstrates that the ATSM encapsulates the common behaviors of any model with at least two active and two inactive conformations: the "states" of the model represent ensembles of active and inactive conformations. A matrix representation of multiconformational models is introduced to provide a compact notation for models with arbitrarily large numbers of conformations. Allosteric modulation is further explored in the context of an operational model of receptor activity which includes constitutive receptor activity. Fitting this model allows the apparent affinity, intrinsic efficacy, and cooperativity constants of a pair of allosteric ligands to be determined. It is also demonstrated that, within certain limits, it is possible to estimate the parameters of the ATSM. Finally, a novel operational model is developed that may allow the analysis of protean ligands. This model requires a nonlinear stimulus function and two parameters to define the efficacy of a ligand. Expressions describing competitive and allosteric interactions under this model are developed and the results of applying null analyses to the data are determined.