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Review
. 2014 Mar;171(5):1102-13.
doi: 10.1111/bph.12345.

Allosteric interactions at adenosine A(1) and A(3) receptors: new insights into the role of small molecules and receptor dimerization

Stephen J Hill  1 , Lauren T May, Barrie Kellam, Jeanette Woolard
Affiliations
Review

Allosteric interactions at adenosine A(1) and A(3) receptors: new insights into the role of small molecules and receptor dimerization

Stephen J Hill et al. Br J Pharmacol. 2014 Mar.

Abstract

The purine nucleoside adenosine is present in all cells in tightly regulated concentrations. It is released under a variety of physiological and pathophysiological conditions to facilitate protection and regeneration of tissues. Adenosine acts via specific GPCRs to either stimulate cyclic AMP formation, as exemplified by Gs -protein-coupled adenosine receptors (A2A and A2B ), or inhibit AC activity, in the case of Gi/o -coupled adenosine receptors (A1 and A3 ). Recent advances in our understanding of GPCR structure have provided insights into the conformational changes that occur during receptor activation following binding of agonists to orthosteric (i.e. at the same binding site as an endogenous modulator) and allosteric regulators to allosteric sites (i.e. at a site that is topographically distinct from the endogenous modulator). Binding of drugs to allosteric sites may lead to changes in affinity or efficacy, and affords considerable potential for increased selectivity in new drug development. Herein, we provide an overview of the properties of selective allosteric regulators of the adenosine A1 and A3 receptors, focusing on the impact of receptor dimerization, mechanistic approaches to single-cell ligand-binding kinetics and the effects of A1 - and A3 -receptor allosteric modulators on in vivo pharmacology.

Keywords: GPCR; adenosine; allosterism; biased signalling; dimerization; receptor.

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Figures

Figure 1
Figure 1
Schematic representation of allosteric regulation of GPCRs by (A) allosteric ligands, (B) signalling proteins or (C) GPCR dimerization. See text for further explanation.
Figure 2
Figure 2
A selection of adenosine receptor allosteric modulators.
Figure 3
Figure 3
Adenosine mediates a significant enhancement in the dissociation of 30 nM ABA-X-BY630 from the human adenosine A3 receptor. (A) Dissociation of a fluorescent adenosine analogue, ABA-X-BY630 (30 nM), from CHO-A3 cells in the absence or presence of adenosine (1 μM; 10 μM; 100 μM). (B) Concentration dependence of the changes in koff of 30 nM ABA-X-BY630 from CHO-A3 cells in the absence and presence of adenosine. Data points are expressed as mean ± SEM from 3–11 separate experiments; each replicate represents the average fluorescence at the plasma membrane of 10 individual cells. Data taken from May et al. (2011).
Figure 4
Figure 4
The influence of the competitive antagonist, MRS1220, and/or the allosteric ligand, VUF5645, on the dissociation kinetics of the fluorescent adenosine derivative, ABA-X-BY630. ABA-X-BY630 (30 nM) dissociation in the absence and presence of a 1 μM MRS1220, 1 μM VUF5645, or 1 μM MRS1220 and 1 μM VUF5645. Representative data performed in duplicate; each replicate represent the average fluorescence at the plasma membrane of 10 individual cells.
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