TY - JOUR T1 - G Protein-Coupled Receptor Heteromerization: A Role in Allosteric Modulation of Ligand Binding JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1044 LP - 1052 DO - 10.1124/mol.110.070847 VL - 79 IS - 6 AU - Ivone Gomes AU - Adriaan P. IJzerman AU - Kai Ye AU - Emeline L. Maillet AU - Lakshmi A. Devi Y1 - 2011/06/01 UR - http://molpharm.aspetjournals.org/content/79/6/1044.abstract N2 - 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. ER -