Oligomerization of μ- and δ-Opioid Receptors

• Published in: The Journal of biological chemistry Vol. 275; no. 34; p. 26128
• Main Authors: Susan R. George, Theresa Fan, Zhidong Xie, Roderick Tse, Vincent Tam, George Varghese, Brian F. O'Dowd
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 25.08.2000
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M000345200

The existence of dimers and oligomers for many G protein-coupled receptors has been described by us and others. Since many G protein-coupled receptor subtypes are highly homologous to each other, we examined whether closely related receptors may interact with each other directly and thus have the potential to create novel signaling units. Using μ- and δ-opioid receptors, we show that each receptor expressed individually was pharmacologically distinct and could be visualized following electrophoresis as monomers, homodimers, homotetramers, and higher molecular mass oligomers. When μ- and δ-opioid receptors were coexpressed, the highly selective synthetic agonists for each had reduced potency and altered rank order, whereas endomorphin-1 and Leu-enkephalin had enhanced affinity, suggesting the formation of a novel binding pocket. No heterodimers were visualized in the membranes coexpressing μ- and δ-receptors by the methods available. However, hetero-oligomers were identified by the ability to co-immunoprecipitate μ-receptors with δ-receptors and vice versa using differentially epitope-tagged receptors. In contrast to the individually expressed μ- and δ-receptors, the coexpressed receptors showed insensitivity to pertussis toxin and continued signal transduction, likely due to interaction with a different subtype of G protein. In this study, we provide, for the first time, evidence for the direct interaction of μ- and δ-opioid receptors to form oligomers, with the generation of novel pharmacology and G protein coupling properties.