G Protein-Coupled Receptor Heteromerization: A Role in Allosteric Modulation of Ligand Binding

It is becoming increasingly recognized that G protein-coupled receptors physically interact. These interactions may provide a mechanism for allosteric modulation of receptor function. In this study, we examined this possibility by using an established model system of a receptor heteromer consisting of mu and delta opioid receptors. We examined the effect of a number of mu receptor ligands on the binding equilibrium and association and dissociation kinetics of a radiolabeled delta receptor agonist, [H-3]deltorphin II. We also examined the effect of delta receptor ligands on the binding equilibrium and association and dissociation kinetics of a radiolabeled mu receptor agonist, [H-3][D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin ([H-3]DAMGO). We show that mu receptor ligands are capable of allosterically enhancing delta receptor radioligand binding and vice versa. Thus, there is strong positive cooperativity between the two receptor units with remarkable consequences for ligand pharmacology. We find that the data can be simulated by adapting an allosteric receptor model previously developed for small molecules, suggesting that the ligand-occupied protomers function as allosteric modulators of the partner receptor's activity.