Oligomerization of mu- and delta-opioid receptors - Generation of novel functional properties

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 r elated receptors may interact with each other directly and thus have the po tential to create novel signaling units. Using mu- and delta-opioid recepto rs, we show that each receptor expressed individually was pharmacologically distinct and could be visualized following electrophoresis as monomers, ho modimers, homotetramers, and higher molecular mass oligomers. When mu- and delta-opioid receptors were coexpressed, the highly selective synthetic ago nists for each had reduced potency and altered rank order, whereas endomorp hin-1 and Leu-enkephalin had enhanced affinity, suggesting the formation of a novel binding pocket. No heterodimers were visualized in the membranes c oexpressing mu- and delta-receptors by the methods available. However, hete rooligomers were identified by the ability to co-immunoprecipitate mu-recep tors with delta-receptors and vice versa using differentially epitope-tagge d receptors, In contrast to the individually expressed mu- and delta-recept ors, the coexpressed receptors showed insensitivity to pertussis toxin and continued signal transduction, likely due to interaction with a different s ubtype of G protein. In this study, we provide, for the first time, evidenc e for the direct interaction of mu- and delta-opioid receptors to form olig omers, with the generation of novel pharmacology and G protein coupling pro perties.