Cubic ternary complex

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. 

A schematic representation of receptor systems in terms of the cubic ternary complex model is shown in Figure 3.13. The amount of signaling species (as a fraction of total receptor) as defined by the cubic ternary complex model see Section 3.13.8 is expressed as... 

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... 

It can be seen from this equation that maximal constitutive activity need not reach a maximal asymptote of unity. Submaximal constitutive activity has been observed with some receptors with maximal receptor expression [28]. While there is scattered evidence that the cubic ternary complex is operative in some receptor systems, and while it is thermodynamically more complete, it also is heuristic... 

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 cubic ternary complex model considers receptors and G-proteins as a synoptic system with some interactions that do not lead to visible activation. 

The cubic ternary complex model takes into the account the fact that both the active and inactive receptor species must have a finite affinity for G-proteins [26-28], The two receptor species are denoted [Ra] (active state receptor able to activate G-proteins) and [RJ (inactive state receptors). These can form species [R,G] and [RaG] spontaneously, and species [ARiG] and [ARaG] in the presence of ligand. 

Weiss, J. M., Morgan, P. H., Lutz, M. W., and Kenakin, T. P. (1996a). The cubic ternary complex receptor-occupancy model. I. Model description. J. Theroet. Biol. 178 151-167. 

Cubic ternary complex model, a molecular model (J. Their. Biol 178, 151-167, 1996a 178, 169-182, 1996b 181, 381-397, 1996c) describing the coexistence of two receptor states that can interact with both G-proteins and ligands. The receptor/G-protein complexes may or may not produce a physiological response see Chapter 3.11. 

Cubic ternary complex model, 50-52, 56-57 Curve fitting... 

However, based on the concept that GPCRs are able to adopt a variety of conformations, an extended model can also be described, as shown in Figure 2. In this extended cubic ternary complex model of receptor activation and modulation, the receptor can interconvert between an active (R) and an inactive conformation (R), each with a different... 

Figure 2 Representation of a "cubic ternary complex" model of allosteric interaction R, the inactive state of the receptor R, the active state of the receptor A, ligand X, allosteric agent. (From Ref. 14.)...

Weiss JM, Morgan PH, Lutz MW, Kenakin TP (1996) The cubic ternary complex receptor-occupancy model I Model description. J Theor Biol 178(2) 151—167... 

Receptors, like all proteins, are known to spontaneously adopt a variety of conformations, and current concepts of receptor function (e.g., the extended and cubic ternary complex models) are based on the allosteric transitions between multiple conformational states. Some of these conformations are called active because they are able to interact with cellular signal transduction mechanisms (and are the basis of constitutive receptor activity ). If one assumes that different receptor conformations might present different intracellular portions of a... 

Although the ETC model explains most GPCR behavior, a more thermodynamically complete model, the cubic ternary complex (CTC) model (Fig. 6), was subsequently proposed (68-70). This model is merely an extension of the ETC model (that is, the ETC model is one of the subsets making up the CTC model) that allows for the existence of an inactive ternary complex, ARG, although both models similarly predict GPCR behavior. However, at the time of development of the ETC and CTC models, neither specifically accommodated experimental... 

Since it is known that different areas of the cytosolic loops of receptors activate different G proteins [191], it is evident that agonists can stabilize multiple active receptor conformations, thus changing not only the degree, but also the quality of receptor activation [192]. Consequently, three-state to multistate models have been developed. Furthermore, in thermodynamic terms must be a provision for the inactive receptor to also interact with G proteins, which lead to a more complex model for GPCRs, named the cubic ternary complex model [193]. Taking into account the concomitant binding of an orthosteric ligand led to a thermodynamically complete, extended model, named the quaternary complex model [194]. The above mentioned and additional models have been recently reviewed by Maudsley et al. [192], Kenakin et al. [195] and Christopoulos et al. [196]. Therein, the potential for allosteric... 

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