RT Journal Article SR Electronic T1 G Protein-Coupled Receptor Heteromerization: A Role in Allosteric Modulation of Ligand Binding JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1044 OP 1052 DO 10.1124/mol.110.070847 VO 79 IS 6 A1 Gomes, Ivone A1 IJzerman, Adriaan P. A1 Ye, Kai A1 Maillet, Emeline L. A1 Devi, Lakshmi A. YR 2011 UL http://molpharm.aspetjournals.org/content/79/6/1044.abstract AB 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 μ and δ opioid receptors. We examined the effect of a number of μ receptor ligands on the binding equilibrium and association and dissociation kinetics of a radiolabeled δ receptor agonist, [3H]deltorphin II. We also examined the effect of δ receptor ligands on the binding equilibrium and association and dissociation kinetics of a radiolabeled μ receptor agonist, [3H][d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin ([3H]DAMGO). We show that μ receptor ligands are capable of allosterically enhancing δ 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.