Extended ternary complex model

With the experimental observation of constitutive activity for GPCRs by Costa and Herz [2], a modification was needed. Subsequently, Samama and colleagues [3] presented the extended ternary complex model to fill the void. This chapter discusses relevant mathematical models and generally offers a linkage between empirical measures of activity and molecular mechanisms. 

The resulting modification is called the extended ternary complex model [3], which describes the spontaneous formation of active state receptor ([Ra]) from an inactive state receptor ([RJ) according to an allosteric constant (L = [Ra]/[RJ). The active state receptor can form a complex with G-protein ([G]) spontaneously to form RaG, or agonist activation can induce formation of a ternary complex ARaG ... 

The extended ternary complex model can take into account the phenomenon of constitutive receptor activity. In genetically engineered systems where receptors can be expressed in high density, Costa and Herz [2] noted that high levels of receptor expression uncovered the existence of a population of spontaneously active receptors and that these receptors produce an elevated basal response in the system. The relevant factor is the ratio of receptors and G-proteins (i.e., elevated levels of receptor cannot yield constitutive activity in the absence of adequate amounts of G-protein, and vice versa). Constitutive activity (due to the [RaG] species) in the absence of ligand ([A] = 0) is expressed as... 

While the extended ternary complex model accounts for the presence of constitutive receptor activity in the absence of ligands, it is thermodynamically incomplete from the standpoint of the interaction of receptor and G-protein species. Specifically, it must be possible from a thermodynamic point of view for the inactive state receptor (ligand bound and unbound) to interact with G-proteins. The cubic ternary complex model accommodates this possibility [23-25]. From a practical point of view, it allows for the potential of receptors (whether unbound or bound by inverse agonists) to sequester G-proteins into a nonsignaling state. 

There are some specific differences between the cubic and extended ternary complex models in terms of predictions of system and drug behavior. The first is that the receptor, either ligand bound or not bound, can form a complex with the G-protein and that this complex need not signal (i.e., [ARiG] and [RjG]). Under these circumstances an inverse agonist (one that stabilizes the inactive state of the receptor) theoretically can form inactive ternary complexes and thus sequester G-proteins away from signaling pathways. There is evidence that this can occur with cannabi-noid receptor [26]. The cubic ternary complex model also... 

FIGURE 3.13 Major components of the cubic ternary complex model [25-27]. The major difference between this model and the extended ternary complex model is the potential for formation of the [ARjG] complex and the [RiG] complex, both receptor/ G-protein complexes that do not induce dissociation of G-protein subunits and subsequent response. Efficacy terms in this model are a, y, and 5. 

The ternary complex model followed by the extended ternary complex model were devised to describe the action of drugs on G-protein-coupled receptors. 

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]) ... 

Extended ternary complex model, a modification of the original ternary complex model for GPCRs (J. Biol. Chem. 268, 4625-4636, 1993) in which the receptor is allowed to spontaneously form an active state that can then couple to G-proteins and produce a physiological response due to constitutive activity. 

Fig. 5. Conceptual schematic of the receptor conformational states elicited by binding to partial (L, ) or full (Ly) agonists, and a depiction of the correlation between the various conformational states and their ability to bind with G proteins. Solid lines show the conformational distributions hypothesized from soluble ternary complex data analyzed by the simple ternary complex model. When a partial agonist binds with a receptor (L R) in this model, the receptor forms a conformational state which has an intermediate affinity for G protein, consequendy leading to formation of intermediate amounts of L RG. On the other hand, the dotted line represents the potential receptor conformations induced by a partial agonist consistent with the extended ternary complex model, which includes the isomerization of receptor between R and R, the only receptor conformation allowed to bind with G protein. For this model, the interactions of a partial agonist with a receptor would result in two populations of ligand-bound receptors with only one (LR ) able to bind with G protein. The x-axis is analogous to the cooperativity factor a.

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... 

As described by the extended ternary complex model, the extent of constitutive activity observed will vary with the receptor according to the magnitude of L for each receptor. This is shown in Figure 3.12, where the constitutive activity... 

There are some specific differences between the cubic and extended ternary complex models in terms of predictions... 

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