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. 2018 Aug 6;21(10):962–977. doi: 10.1093/ijnp/pyy071

Figure 5.

Figure 5.

Three-state model of receptor function. The simplest multi-active state model of receptor function is the 3-state model, where receptors in a population can adopt either an inactive conformation (R), or 1 of 2 active conformation (R* and R**). As in the 2-state model described in Figure 2, the active receptor conformations, R* and R** are in equilibrium with the inactive conformation (R), as defined by the allosteric transition constants, L and M. The magnitude of response is dependent on the quantity of receptors in an active conformation and the efficiency of receptor-effector coupling (Ke). Thus, the magnitude of constitutive activity can differ for Response 1 vs Response 2, either because L and M are different or Ke1 and Ke2 differ, or both. Ligands have affinity for all 3 receptor conformational states (KA, KA*, and KA**), and ligand efficacy is dependent on the differential affinity values for the 3 conformations. With this model, it is possible that a ligand with disproportionately high affinity for R* vs R and R** could act as a strong agonist for Response 1 (due to enrichment of the R* population), however act as an inverse agonist for Response 2 due to depletion of R**. Thus the same ligand could be simultaneously both an agonist and an inverse agonist, acting via the same receptor. It is important to keep in mind that this model is a pronounced oversimplification on many levels. It is likely that receptors can adopt many more than 3 conformations. Moreover, although this model depicts Response 1 being controlled by R* and Response 2 controlled by R**, it is certainly possible that each active conformation could regulate both responses with different Ke (e.g., Ke1a and Ke1b) values. Also, the model as presented shows that for R* to transition to the R** conformation, it must first become R. This need not happen as it is possible that R* could directly transition to R**. Although likely oversimplified (e.g., Ke associated with R*(*) need not equal Ke associated with AR*(*)), this model was able to account for the behavior of 5-HT2C agonists to differentially regulate PLC and PLA2 signaling (Berg et al., 1998).