Agonist trafficking what do models predict

In the initial model by Kenakin, there is a limitless number of active receptor conformations. For simulation studies, this was simplified by Leff et al. (1997) to three receptor conformations with one inactive (R) and two active conformations (R* and R**). In the intact three-state model (Figure 198), it was further assumed that:

analysis with antagonists = 3 receptor types analysis with antagonists = 3 receptor types

analysis with agonists = 9 receptor types

Figure 197 Schematic diagram of three receptors interacting with three G proteins. Antagonists would recognize three 'receptor types', while agonists would recognize up to nine 'receptor types'. Reproduced from Kenakin, T. (1996) Pharmacological Reviews, 48, 413-463, with permission from the American Society for Pharmacology and Experimental Therapeutics.

Ul Hi Ui analysis with agonists = 9 receptor types

Figure 197 Schematic diagram of three receptors interacting with three G proteins. Antagonists would recognize three 'receptor types', while agonists would recognize up to nine 'receptor types'. Reproduced from Kenakin, T. (1996) Pharmacological Reviews, 48, 413-463, with permission from the American Society for Pharmacology and Experimental Therapeutics.

• The AR* and AR** formations are linked to each other. Enrichment of one active conformation will be at the expense of the other.

• The amount of receptors in each active conformation (i.e. [R*] + [AR*] on one hand and [R**] + [AR**] on the other hand) represent a 'stimulus'. Obviously, these stimuli do not represent the ultimate effects/responses of the receptor. To 'transpose' stimuli into responses, one may have to take account of potential pathway-related differences in 'receptor reserve'.

• In each active conformation, the receptor is able to couple to a distinct type of G protein.

• The receptors and G proteins have free access to one another (i.e. no membrane compartmentalization).

Figure 198 Intact three-state model describing the linked formation of AR* and AR**. Reprinted from Trends in Pharmacological Science, 18, Leff, P., Scaramellini, C., Law, C. and McKechnie, K., A three-state receptor model of agonist action, 355-362. Copyright (1997), with permission from Elsevier.

Figure 199 Simulations of agonist behaviour according to the intact three-state model. fR. or fR.. = fraction of receptors in active conformation(s). Reprinted from Trends in Pharmacological Science, 18, Leff, P., Scaramellini, C., Law, C. and McKechnie, K., A three-state receptor model of agonist action, 355-362. Copyright (1997), with permission from Elsevier.

Figure 199 Simulations of agonist behaviour according to the intact three-state model. fR. or fR.. = fraction of receptors in active conformation(s). Reprinted from Trends in Pharmacological Science, 18, Leff, P., Scaramellini, C., Law, C. and McKechnie, K., A three-state receptor model of agonist action, 355-362. Copyright (1997), with permission from Elsevier.

Simulations according to this intact three-state model (Figure 199) reveal that, while agonist trafficking may produce differences in ligand intrinsic efficacy orders and even that agonists for one type of response may behave as inverse agonists for the other response, each ligand should increase the AR* and AR** concentrations with the same potency. Hence, these simulations suggest that the rank order of agonist efficacies at the same receptor can differ from one response pathway to another. This constitutes a major break with the traditional receptor theory in which only a single active receptor conformation is allowed to exist.

Yet the rank order of agonist potencies may vary among response pathways if one considers that AR* and AR** are formed independently of one another (Figure 200). Under these conditions, the three-state model is actually composed of two pathways which operate in an isolated manner, one dealing with the R* conformation and the other dealing with the R** conformation.

Obviously, splitting of the intact three-state model into two independent two-state models implies that the AR* and AR** formations are no longer linked to one another. How can a receptor molecule be prevented from adopting a particular active conformation even before coupling is allowed to take place? One way to overcome this caveat is to change the premise of the three-state model by assuming that receptors are pre-coupled to G proteins and that pre-coupling influences the 'energy landscape' of the receptor. According to this view, the stimulus no longer reflects the concentration of activated receptors, but rather the concentration of activated receptor-G protein complexes.

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