Trends in Pharmacological Sciences
A three-state receptor model of agonist action
Section snippets
Derivation of the model
The two-state model of agonist action[8]is illustrated in Fig. 1. In order to account for multiple receptor–effector coupling, it may be assumed that the active form of the receptor, R*, is able to activate more than one G protein. Fig. 1 illustrates the case for two different G proteins. However, we would argue that this would not allow for altered pharmacology to be expressed through the different pathways. The reason for this is that, in the two-state model, agonists act by enriching R*,
Predictions of the model
, , , were used to simulate agonist concentration–effect {E/[A]} curves under different theoretical conditions. To do this it was assumed that the fraction of receptors in the R* state represents the output of the model through the G1-linked pathway, and that the fraction of receptors in the R** state represents the output of the system through the G2-linked pathway. In other words, no post-receptor coupling or `receptor reserve' was included in the model. This was a deliberate, simplifying
Analysis of experimental data
In this section the three-state model is applied to account for experimental data obtained in promiscuous receptor systems. Two examples are considered. They are similar in that they both involve a single type of receptor coupled to two different G proteins and in each case, the two biochemical responses have distinct agonist pharmacology. However, the pattern of altered agonist pharmacology is different in the two cases.
The first example concerns human 5-HT2C receptors (unpublished data,
Mechanistic considerations
In the foregoing sections, we have considered the operation of the three-state model, and its ability to account for experimental data, in two modes, intact and isolated. It is important to give some attention to the mechanistic circumstances in which the two modes may be expected to apply.
The intact mode would be assumed to operate when the responses through different biochemical pathways are measured in the same cell under the same experimental conditions. Under these conditions, the
Concluding remarks
The three-state model of receptor activation constitutes a relatively simple but flexible scheme for predicting and analysing the interaction of agonists with promiscuous receptor systems. The model predicts that agonists can exhibit a wide range of activities, including alterations in potency and efficacy orders amongst systems containing the same receptor type. These changes can arise from differences in assay system, the response measured, or the level of constitutive activity. Traditionally
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2016, Biophysical JournalCitation Excerpt :However, a fundamental distinction can be made by asking whether their formation reflects “conformations induced” by the particular biased agonist (2) or stabilization of a small number of discrete preexisting conformations consistent with the Monod-Wyman-Changeux (MWC) allosteric model (7). Although particular features of GPCRs have been interpreted using allosteric concepts (8–11), a global allosteric formalism that explores the full range of allosteric linkages in the original MWC framework (7,12) is considered here. This formalism includes local steric competition between G-proteins and β-arrestin, as well as reciprocal effects that govern the potentiation of these two proteins on the corresponding agonist affinities.