RT Journal Article
SR Electronic
T1 G protein-coupled receptor heterodimerization: A role in allosteric modulation of ligand-mediated receptor binding
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.070847
DO 10.1124/mol.110.070847
A1 IVONE GOMES
A1 Adriaan P. IJzerman
A1 Kai Ye
A1 Emeline L Maillet
A1 Lakshmi A. Devi
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/03/17/mol.110.070847.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, association and dissociation kinetics of a radiolabeled δ receptor agonist, [3H]Deltorphin II. Reciprocally, we also examined the effect of δ receptor ligands on the binding equilibrium, association and dissociation kinetics of a radiolabeled μ receptor agonist, [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.