A Role for the Distal Carboxyl Tails in Generating the Novel Pharmacology and G Protein Activation Profile of μ and δ Opioid Receptor Hetero-oligomers

Abstract

Opioid receptor pharmacology in vivo has predicted a greater number of receptor subtypes than explained by the profiles of the three cloned opioid receptors, and the functional dependence of the receptors on each other shown in gene-deleted animal models remains unexplained. One mechanism for such findings is the generation of novel signaling complexes by receptor hetero-oligomerization, which we previously showed results in significantly different pharmacology for and ␦ receptor hetero-oligomers compared with the individual receptors. In the present study, we show that deltorphin-II is a fully functional agonist of the -␦ heteromer, which induced desensitization and inhibited adenylyl cyclase through a pertussis toxin-insensitive G protein. Activation of the -␦ receptor heteromer resulted in preferential activation of G␣ z , illustrated by incorporation of GTP␥ 35 S, whereas activation of the individually expressed and ␦ receptors preferentially activated G␣ i . The unique pharmacology of the -␦ heteromer was dependent on the reciprocal involvement of the distal carboxyl tails of both receptors, so that truncation of the distal receptor carboxyl tail modified the ␦-selective ligand-binding pocket, and truncation of the ␦ receptor distal carboxyl tail modified the -selective binding pocket. The distal carboxyl tails of both receptors also had a significant role in receptor interaction, as evidenced by the reduced ability to co-immunoprecipitate when the carboxyl tails were truncated. The interaction between and ␦ receptors occurred constitutively when the receptors were co-expressed, but did not occur when receptor expression was temporally separated, indicating that the hetero-oligomers were generated by a co-translational mechanism.The endogenous opioid systems mediate important physiological functions related to pain perception, locomotion, motivation, reward, autonomic function, immune modulation, and hormone secretion. Opioid receptors, mediating the actions of the opioid peptides, belong to the family of G protein-coupled receptors (GPCRs) 2 and have distinct pharmacological profiles with discrete but overlapping distributions in brain (reviewed Refs. 1 and 2). The pharmacology of the opioid receptors obtained in brain and other tissues has consistently predicted a greater number of receptor subtypes such as 1, 2, and ␦1, ␦2, which are not explained by the individual pharmacological profiles obtained for the three cloned opioid receptors, , ␦, and , when expressed individually in heterologous systems. One possible mechanism for these findings, gaining increasing credence, has been that of direct receptorreceptor interactions creating novel signaling units and generating distinct post-receptor functional effects.The ability of GPCRs to form homo-oligomers and hetero-oligomers has been described by us and others (reviewed in Refs. 3-5). We have provided evidence for the direct interaction of and ␦ opioid receptors to form hetero-oligomers, with generation of novel pharmacology and G protein coupling properti...

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

“…7 In recent years, several studies have shown that and ␦ receptors form functionally distinct heterodimeric or hetero-oligomeric complexes. [8][9][10][11] The physiological and pharmacological signifi cance of -␦ interactions have been substantiated by recent studies using opioid receptor gene knockout animals. 12 The existence of intermodulatory effects between and ␦ receptors has spawned a new interest in the pursuit of ligands with a mixed interaction profi le at the and ␦ receptors as a novel therapeutic approach for the treatment of pain.…”

G-Protein Coupled Receptors Dimerization: Diversity in Somatostatin Receptors Subtypes

“…Most importantly, the ability of SSTR4 to form homodimer was not observed with the C-tail of SSTR1 [106]. The specificity of the C-tail in the process of dimerization is not restricted to SSTR subtypes only but was also described for δ-opioid receptor-trafficking and heterodimerization of GABABR subtypes GABABR1 and GABABR2 [34,37], and for μ-and δ-opioid receptor (ORs) heterodimerization [121]. SSTR1/SSTR5 heterodimerization leads to greater efficiency in signaling and inhibition of adenylate cyclase and cAMP synthesis [65].…”

Sélectivité fonctionnelle des ligands des récepteurs opiacés

“…Les propriétés pharmacologiques et signalétiques des récepteurs opiacés peuvent en effet varier en fonction du profil d'expression protéique qui est spécifique à chaque type cellulaire. Différents partenaires de dimérisation peuvent ainsi modifier les propriétés pharmacologiques des récepteurs [24,25]. Pourtant, si aucune inversion de l'ordre d'efficacité et/ou de puissance des ligands n'est observée, ces modifications ne constituent pas une preuve irréfutable de la présence de conformations actives spécifiques aux ligands.…”

“…Pourtant, si aucune inversion de l'ordre d'efficacité et/ou de puissance des ligands n'est observée, ces modifications ne constituent pas une preuve irréfutable de la présence de conformations actives spécifiques aux ligands. L'hétérodimérisation DOR/MOR, par exemple, produit un changement de couplage du DOR de Gi3 vers Gz, mais le DPDPE reste plus efficace que la deltorphine II pour activer les différentes sous-unités G [25]. Par ailleurs, la sélectivité fonctionnelle ne se limite pas à produire l'activation de différentes sous-unités G.…”