Two-state receptor model

Figure 7 The two-state receptor model L = ligand, R = inactive GPCR, andR = active GPCR...

Receptor inactivation theory, initially proposed by Gosselin in 1977 has been widely disseminated by Kenakin (35)and to some degree is based on the two-state model originally proposed by Katz and Thesleff (41) for ion channels, specifically the Torpedo nicotinic receptor. where the multimeric receptor exists in active and inactive states, with ligand binding altering the equilibrium between these two states. Receptor inactivation theory reflects a synthesis of both occupancy and rate theories providing an alternative consideration for the study of the RL interaction. 

The extended ternary complex model [23] was conceived after it was clear that receptors could spontaneously activate G-proteins in the absence of agonist. It is an amalgam of the ternary complex model [12] and two-state theory that allows proteins to spontaneously exist in two conformations, each having different properties with respect to other proteins and to ligands. Thus, two receptor species are described [Ra] (active state receptor able to activate G-proteins) and [RJ (inactive state receptors). These coexist according to an allosteric constant (L = [Ra]/[Ri]) ... 

Two-state model, a model of proteins that coexists in two states controlled by an equilibrium constant. Molecules with selective affinity for one of the states will produce a bias in that state upon binding to the system. Two-state theory was conceived to describe the function of ion channels but also has relevance to receptors (see Chapter 3.7). 

In the simple two-state model shown in equation (A3.1) the receptor can only exist in either free or bound states and so... 

The term state rather than condition is often used in this context. However, the latter seems preferable in an introductory account. This is because the del Castillo-Katz mechanism is often described as a two-state model of receptor action, meaning here that the occupied receptor exists in two distinct (albeit interconvertible) forms, AR and AR, whereas three conditions of the receptor (R, AR, and AR ) have to be identified when applying the law of mass action to the binding of the ligand, A. 

In contrast to the assumption made in the classical occupation theory, the agonist in the two-state model does not activate the receptor but shifts the equilibrium toward the R form. This explains why the number of occupied receptors does not equal the number of activated receptors. 

Leff, P. (1995). The two-state model of receptor activation [see comments]. Trends Pharmacol. Sci. 16, 89-97. 

While occupancy theory is far and away the most widely used model for describing dose-response curves, other theories do exist. One example is allosteric theory. At the center of allosteric theory, sometimes called the two-state model, is the idea that a receptor can exist in conformations that either cause a response (relaxed state) or do not cause a response (tensed state).29 These conformations, represented by T and R, are in equilibrium (Scheme 5.7). 

Solid state analysis of crystals obtained of receptor with acetate from water/methanol solutions reveal that once again the guanidiniocarbonylpyrrole cation exists in an extended conformation however in contrast to the proposed solution state model, the pyrrole NH points away from the guanidium NHs with the acetate anions bound by two separate receptor groups with solvent molecules helping to create a series of 2D arrays (figure 23c). 

Formally, the extended ternary complex model is a two-state model different agonists apparently produce cellular response by causing (quantitatively different) enrichment of the (qualitatively identical) R active receptor conformation. However, upon more careful examination it becomes clear that the allosteric constants a and/or (3 can theoretically be specific for each ligand [42], Under these circumstances the ternary complex... 

Partial agonism and the two-state model of receptor activation... 

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