Receptors allosteric theory

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). 

The binding of a ligand to a receptor shifts the position of the equilibrium. According to allosteric theory, agonists stabilize the relaxed conformation. The equilibrium shifts to the left, and the response increases. Inverse agonists stabilize the tensed conformation and decrease the baseline response. Antagonists bind both conformations equally and do not shift the equilibrium from its original position. 

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]) ... 

After the formation of an RL eomplex, a functional response to receptor activation can be related to the concentration of the ligand present (Fig. 10.1a). Occupancy theory, developed by Clark in 1926 (22), is based on a dose/ concentration-response relationship. This theory has undergone eontinuous refinement based on experimental data to aid in further delineating the increasingly complex coneept of ligand efficacy (23) and to accommodate allosteric site modulation of receptor function (21,24,25), ternary complex models, (26,27) and their extension to constitutively active re-... 

Allosteric modulation of seven transmembrane spanning receptors Theory, practice, and opportunities for central nervous system dmg discovery 12JMC1445. 

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