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

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 μ and δ receptor hetero-oligomers compared with the individual receptors. In the present study, we show that deltorphin-II is a fully functional agonist of the μ-δ heteromer, which induced desensitization and inhibited adenylyl cyclase through a pertussis toxin-insensitive G protein. Activation of the μ-δ receptor heteromer resulted in preferential activation of Gαz, illustrated by incorporation of GTPγ35S, whereas activation of the individually expressed μ and δ receptors preferentially activated Gαi. The unique pharmacology of the μ-δ heteromer was dependent on the reciprocal involvement of the distal carboxyl tails of both receptors, so that truncation of the distal μ receptor carboxyl tail modified the δ-selective ligand-binding pocket, and truncation of the δ receptor distal carboxyl tail modified the μ-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 μ and δ 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. 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 μ and δ receptor hetero-oligomers compared with the individual receptors. In the present study, we show that deltorphin-II is a fully functional agonist of the μ-δ heteromer, which induced desensitization and inhibited adenylyl cyclase through a pertussis toxin-insensitive G protein. Activation of the μ-δ receptor heteromer resulted in preferential activation of Gαz, illustrated by incorporation of GTPγ35S, whereas activation of the individually expressed μ and δ receptors preferentially activated Gαi. The unique pharmacology of the μ-δ heteromer was dependent on the reciprocal involvement of the distal carboxyl tails of both receptors, so that truncation of the distal μ receptor carboxyl tail modified the δ-selective ligand-binding pocket, and truncation of the δ receptor distal carboxyl tail modified the μ-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 μ and δ 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) 2The abbreviations used are: GPCR, G protein-coupled receptor; DAMGO, [d-Ala2, NMePhe4, Gly-ol5]enkephalin; DPDPE, [d-Pen2,d-Pen5]enkephalin, DSLET, [d-Ser2, Leu5]enkephalin-Thr6, PTX, pertussis toxin; GTPγS, guanosine 5′-3-O-(thio)triphosphate; TRITC, tetramethylrhodamine isothiocyanate. and have distinct pharmacological profiles with discrete but overlapping distributions in brain (reviewed Refs. 1.Lev ac B.A.R. O'Dowd B.F. George S.R. Curr. Opin. Endocrinol. Diabetes. 2001; 8: 166-171Crossref Scopus (2) Google Scholar and 2.Lev ac B.A. O'Dowd B.F. George S.R. Curr. Opin. Pharmacol. 2002; 2: 76-81Crossref PubMed Scopus (123) Google Scholar). The pharmacology of the opioid receptors obtained in brain and other tissues has consistently predicted a greater number of receptor subtypes such as μ1, μ2, and δ1, δ2, which are not explained by the individual pharmacological profiles obtained for the three cloned opioid receptors, μ, δ, and κ, when expressed individually in heterologous systems. One possible mechanism for these findings, gaining increasing credence, has been that of direct receptor-receptor 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.Milligan G. Mol. Pharmacol. 2004; 66: 1-7Crossref PubMed Scopus (421) Google Scholar, 4.George S.R. O'Dowd B.F. Lee S.P. Nat. Rev. Drug Discov. 2002; 1: 808-820Crossref PubMed Scopus (546) Google Scholar, 5.Bouvier M. Nat. Rev. Neurosci. 2001; 2: 274-286Crossref PubMed Scopus (584) Google Scholar). We have provided evidence for the direct interaction of μ and δ opioid receptors to form hetero-oligomers, with generation of novel pharmacology and G protein coupling properties, distinct from that demonstrated when each receptor was expressed individually (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar). Novel functional properties generated by the formation of hetero-oligomeric opioid receptor complexes have been reported for μ and δ opioid receptors (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar, 7.Gomes I. Jordan B.A. Gupta A. Trapaidze N. Nagy V. Devi L.A. J. Neurosci. 2000; 20: 1-5Crossref PubMed Google Scholar) and δ and κ opioid receptors (8.Jordan B.A. Devi L.A. Nature. 1999; 399: 697-700Crossref PubMed Scopus (982) Google Scholar). Receptor homo-oligomerization appears to be a universal occurrence for GPCRs, with functional roles emerging in cellular processes such as receptor trafficking after synthesis in the endoplasmic reticulum (9.Lee S.P. O'Dowd B.F. Ng G.Y. Varghese G. Akil H. Mansour A. Nguyen T. George S.R. Mol. Pharmacol. 2000; 58: 120-128Crossref PubMed Scopus (145) Google Scholar). The functional roles for hetero-oligomerization of GPCRs appear varied, ranging from chaperone-like aiding of cell surface localization to novel pharmacology and signal transduction properties, depending on the interacting receptors (4.George S.R. O'Dowd B.F. Lee S.P. Nat. Rev. Drug Discov. 2002; 1: 808-820Crossref PubMed Scopus (546) Google Scholar). μ and δ opioid receptors share and greater in the ac B.A.R. O'Dowd B.F. George S.R. Curr. Opin. Endocrinol. Diabetes. 2001; 8: 166-171Crossref Scopus (2) Google Scholar). We have previously shown that the receptors expressed individually and whereas μ and δ receptors did not form (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google a different interaction between The receptors were shown to have significant of individual pharmacology and signal transduction properties, with the of unique properties (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar, 7.Gomes I. Jordan B.A. Gupta A. Trapaidze N. Nagy V. Devi L.A. J. Neurosci. 2000; 20: 1-5Crossref PubMed Google Scholar) and signaling functions Mol. Pharmacol. 2000; Scopus Google Scholar). In the present study, we to the in the pharmacology and signaling from the formation of the μ-δ hetero-oligomeric and to a agonist for the We also to the for the receptor-receptor interaction, which has not been We demonstrated that deltorphin-II was agonist of the μ-δ heteromer, of desensitization and the pertussis toxin-insensitive protein whereas agonist activation of the individual μ and δ receptors activated the pertussis We also that the distal carboxyl tails of both receptors in the for the generation of the unique pharmacology of the μ and δ heteromer and had a significant role in the interaction between the receptors. of μ and δ Opioid Receptor the μ and δ opioid receptors were the expression as previously described M. Nat. Rev. Neurosci. 2001; 2: 274-286Crossref PubMed Scopus (584) Google Scholar). the receptors were with the also as described M. Nat. Rev. Neurosci. 2001; 2: 274-286Crossref PubMed Scopus (584) Google Scholar). 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Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google that a interaction mediate the formation of compared with the formation of receptor of the δ receptor was by with the μ opioid receptor (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar) and the of the δ receptor has been to the distal carboxyl tail Devi J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (421) Google we that the interaction between μ and δ opioid receptors the carboxyl tail of the δ The had different for the individually expressed and μ and δ receptors as shown The of the carboxyl tail of the δ opioid receptor from to were and was of the μ opioid receptor with the receptor the of the μ-selective agonist DAMGO, the a truncation have a was to the of with the μ opioid receptor of the binding to both the and of the μ opioid receptor and binding of these that both were expressed in that the of the carboxyl tail of the δ receptor of μ opioid pharmacology when the receptors were the of the μ receptor with the truncation of the δ receptor the of by of a μ opioid binding pocket. the pharmacology of the and receptors by when expressed with the μ opioid receptor was to that of the δ of the truncation of the carboxyl tail and of truncation of the distal carboxyl tail of the δ opioid receptor on the δ-selective agonist μ and δ receptors. The the δ receptor were with the μ opioid were and by shown are of the carboxyl tail of the μ opioid receptor also had role in the pharmacology of the μ-δ of the μ opioid receptor with that for the δ receptor were The distal to in the carboxyl tail and the distal to in the carboxyl tail were of these μ receptor truncation with the δ opioid receptor of with to the but of of the results that truncation of the carboxyl tail of μ and δ opioid receptors resulted in and δ-selective pharmacology when the receptors were the carboxyl tails of the μ and δ opioid receptors have been shown to have a role in the novel pharmacology generated by to be the interaction between these receptors the carboxyl μ and δ opioid receptors be with each other and of the carboxyl and receptors of ability to form indicating that the carboxyl tails were not important of the receptor-receptor interactions of μ δ opioid receptors. the ability of μ receptors to with each other was not by truncation of the carboxyl tail not when the μ opioid receptor was with the receptors, of was and compared with the receptors and results that the carboxyl tails are important of the μ-δ receptor but are not the of between μ and δ receptors. we have previously shown that μ and δ opioid receptors resulted in of distinct pharmacological profiles by the in to the of the receptors in the (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google we the of synthesis of the receptors the The of μ and δ opioid receptors was compared with of these receptors. The of for the μ opioid receptor when was by was in the for the as is for μ opioid receptors expressed with a for the μ-δ heteromer when the receptors were the for binding when μ and δ receptor was was to the when the receptors were results were obtained when the of the was The cellular of μ and δ receptors was by receptors were to have the on the cell surface and in the when when was results that the receptor interaction and not the cell demonstrated that receptors the cellular interacting with each The interaction between μ and δ opioid receptors generating novel pharmacological and functional properties formation of a unique signaling distinct from that present when the receptors are expressed We have that deltorphin-II is a agonist the μ-δ with of agonist binding that were to and desensitization on agonist by to a In the μ-δ deltorphin-II these agonist through the involvement of a G The from activation by agonist interaction of μ and δ receptor homo-oligomers to activation by μ-δ heteromer activation the of a in G protein for a hetero-oligomeric receptor to that is different from the of that of receptor We also that the for the μ-δ interaction in the distal of the carboxyl tails of both μ and δ receptors as for generating the novel pharmacological of the The carboxyl tail interaction was also for the of μ and δ receptors but not for the of opioid receptor pharmacology has provided evidence for the of a and pharmacology in different tissues A. M. H. J. Pharmacol. Google Scholar, H. J. R. PubMed Scopus Google which the of the opioid receptors, was to be of the formation of between distinct opioid receptor J. J. Pharmacol. Full Text PDF PubMed Scopus Google Scholar). we and others showed in the for these be the hetero-oligomerization of μ and δ opioid receptors (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar, 7.Gomes I. Jordan B.A. Gupta A. Trapaidze N. Nagy V. Devi L.A. J. Neurosci. 2000; 20: 1-5Crossref PubMed Google Scholar). the had demonstrated the greater of such as deltorphin-II than A. M. H. J. Pharmacol. Google Scholar, H. J. R. PubMed Scopus Google which findings the agonist of the μ and δ receptors that described for the pharmacological but to the pharmacological have been demonstrated I. Jordan B.A. Gupta A. Trapaidze N. Nagy V. Devi L.A. J. Neurosci. 2000; 20: 1-5Crossref PubMed Google which the that the μ-δ heteromer the previously opioid receptor in In deltorphin-II appears to as a agonist the μ-δ as evidenced by the of receptors in a to and evidence of desensitization and with to The novel pharmacological obtained with the μ and δ receptors that the binding of each receptor had been In both and DPDPE, to be μ-selective and δ-selective had but for the μ-δ receptors. The ability of deltorphin-II to as agonist with pertussis that the μ-δ receptors were with a G protein. the interactions of μ and δ opioid receptors with G we the of to and from the receptors, and demonstrated that adenylyl cyclase signaling the μ-δ opioid receptors after The ability of deltorphin-II to adenylyl cyclase after of μ-δ receptors that the coupling in of adenylyl cyclase was by a G J. T. M. Z. Mol. 1999; PubMed Scopus Google Scholar). opioid receptors have the ability to to G J. M. J. Neurosci. PubMed Scopus Google Scholar, J. A. V. J. 1999; PubMed Scopus Google we have shown previously for the μ opioid that of the by results in of the with of receptors to the Devi J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (421) Google Scholar, O'Dowd B.F. George S.R. J. Biol. Chem. 1999; Scholar). we have shown that adenylyl cyclase by μ δ opioid receptors is by with (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google indicating preferential coupling to when μ δ receptors are expressed In of these findings, we that the agonist obtained the of these for the μ-δ heteromer to the novel G protein. The of obtained after deltorphin-II is unique to the μ-δ The of these for adenylyl cyclase that the μ-δ we have provided evidence for the direct incorporation of by deltorphin-II activation of the μ-δ heteromer, in to the preferential incorporation of when agonist activation of the individual μ and δ receptors The of novel G protein coupling by the μ and δ receptors and of the of δ opioid receptor by a δ agonist when the receptor was with μ receptors (6.George S.R. Fan T. Xie Z. Tse R. Tam V. Varghese G. O'Dowd B.F. J. Biol. Chem. 2000; 275: 26128-26135Abstract Full Text Full Text PDF PubMed Scopus (507) Google us to that the of these receptors have induced in the of the μ and δ receptors. the of the findings that the binding and the of the of the μ-δ from that in the receptor In the carboxyl tails of GPCRs have been shown to have important functional roles in mediating of the for receptor Pharmacol. Rev. 2001; Google Scholar, Nat. Rev. Neurosci. 2001; 2: PubMed Scopus Google Scholar). of the carboxyl tail and have been for both μ O'Dowd B.F. George S.R. J. Biol. Chem. 1999; Scholar, T. M. M. H. V. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, O'Dowd B.F. George S.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and δ N. Devi L.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) receptors as important for We that the of the δ receptor to when with the μ receptor that the of the carboxyl tail that δ opioid receptor was we the distal of the δ opioid receptor carboxyl and a of to that of these the μ opioid receptor pharmacology in the receptors, indicating that the carboxyl tail of the δ opioid receptor was in mediating the to the binding of the μ opioid the was not fully by were also in the μ opioid the μ receptor truncation were with the δ opioid the indicating that the carboxyl tail of the μ receptor had to the of the binding in the δ that the carboxyl tails of both receptors were in generating the novel pharmacology of the μ-δ The of the distal of the carboxyl tails to the ability of the receptors to was of the δ and μ truncation when expressed and in to has been reported for the δ opioid receptor in the Devi J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (421) Google Scholar). show that the carboxyl tails had role in generating the of μ δ opioid receptors. The reduced ability of the δ receptor to co-immunoprecipitate with the μ receptor and that the interactions the carboxyl tail were significant in the interactions between μ and δ receptors in other are present as was not The μ-δ interaction occurred when the receptors were indicating that the formation of the hetero-oligomers occurred after The expression of the receptors by and resulted in the pharmacological of μ and δ The of μ and δ opioid receptor such as shown in models of I. M. G. J. Pharmacol. Scopus Google A. M. H. J. Pharmacol. Google and M. A. J. Pharmacol. Google Scholar, A. J. J. Pharmacol. Google Scholar, M. A. J. M. R. G. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Lee J. 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PubMed Scopus Google to significant physiological functional interactions between μ and δ opioid receptors. a cellular has been shown that μ and δ receptors the PubMed Scopus Google and that of with the μ-selective agonist of δ receptors to the cell surface A. Lee A. J. Neurosci. 2001; PubMed Google indicating that the cellular trafficking of the δ receptor be by activation of the μ opioid receptor In we have shown that the between μ and δ opioid receptors a distinct and novel which results from interactions by the distal carboxyl tails of the receptors. The of deltorphin-II as agonist of the and the novel of receptor with a G protein as the formation of a signaling different from that present when μ δ receptor homo-oligomers are individually The hetero-oligomerization of μ and δ opioid receptors the of signal transduction to these receptors and a novel for the and of opioid The hetero-oligomerization of μ and δ opioid receptors to a unique signaling also has significant for a novel and which have physiological in processes such as and

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