Allosteric theory: taking therapeutic advantage of the malleable nature of GPCRs

Abstract

The description of the allosteric modification of receptors to affect changes in their function requires a model that considers the effects of the modulator on both agonist affinity and efficacy. A model is presented which describes changes in affinity in terms of the constant alpha (ratio of affinity in the presence vs the absence of modulator) and also the constant xi (ratio of intrinsic efficacy of the agonist in the presence vs absence of modulator). This allows independent effects of both affinity and efficacy and allows the modeling of any change in the dose-response curve to an agonist after treatment with modulator. Examples are given where this type of model can predict effects of modulators that reduce efficacy but actually increase affinity of agonist (i.e. ifenprodil) and also of modulators that block the action of some agonists (the CXCR4 agonist SDF-1alpha by the antagonist AMD3100) but not others for the same receptor (SDF-1alpha peptide fragments RSVM and ASLW).'All models are wrong...but some are useful...'anonymous environmental scientist.

Fig. (1)

A sampling of the many possible effects allosteric modulators may have on the concentration-response curve to an agonist. Independent increases or decreases in the location parameter and maximal abscissae of these curves as well as incomplete saturable effects (limited shifts of the curve or changes in maxima) are possible. In effect, the allosteric modulator theoretically can create a completely new receptor with unique responsiveness to various probes such as agonists and/or radioligands.

Fig. (2)

A simple theoretical model of allosteric receptor function whereby the receptor activates cellular response machinery according to an operational equilibrium dissociation constant K_E under normal circumstances and with a dissociation constant K^’_E when bound to the allosteric modulator.

Fig. (3)

Effects of different modulators on agonist response according to the model depicted in Fig. (2). Changes in affinity (α) only produce changes in the location parameter of the concentration-response curves but no change in maxima. Modulator-induced changes in efficacy (ξ) can alter location parameters and maximal response. For allosteric potentiation of response, only changes in location are observed for full agonists For partial agonists, changes in maxima can be seen. In cases of allosteric reduction in efficacy, both changes in location and maxima may be observed.

Fig. (4)

The Hall model [20] of allosteric function whereby the effect of the modulator on agonist-induced (A) or spontaneously formed active state receptor is affected by binding of the modulator (B). Shaded squares represent the respective species measured in functional and binding experiments. The fact that these species are different for the assay types leaves open the possibility that different responses to allosteric modulators may be observed in these two different assay formats.

Fig. (5)

Effects of allosteric modulators on agonist response. A. Effect of Sch-C on CCR5-mediated calcium responses to the chemokine RANTES. Curves shown in the absence (filled circles) and presence of Sch-C (17.6 nM; filled diamonds : 26.3 nM filled triangles). Open squares indicate half maximal location parameters of the curves; note the dextral displacement with antagonsm by Sch-C. B. Blockade of NMDA responses of rat cortical neurons by Ifenprodil. Curves shown in the absence (filled circles) nnd presence of ifenprodil (0.1 μM, filled diamonds: 1 μM, filled triangles). Open squares indicate half maximal location parameters for the concentration-response curves; note the sinistral displacement with increasing concentrations of ifenprodil. Data redrawn from [29].

Fig. (6)

Inhibition of the effects of two concentrations of NMDA (see Fig. 5) by ifenprodil. It can be seen that the IC₅₀ of ifenprodil for NMDA inhibition actually decreases with increasing concentrations of NMDA (the potency of ifenprodil is greater blocking 100 µM NMDA as compared to 10 μM NMDA). Data redrawn from [29].

Fig. (7)

Displacement of bound ¹²⁵I-MIP-1α from chemokine C receptors type 1 (CCR1) by MIP-1α (filled triangles) and the allosteric ligand UCB35625 (open triangles). Incomplete displacement indicates an allosteric resetting of the affinity of the receptor for MIP-1α. Redrawn from [45].