title: Trafficking of preassembled opioid mu-delta heterooligomer-Gz signaling complexes to the plasma membrane: coregulation by agonists.
abstract: The cellular site of formation, Galpha-coupling preference, and agonist regulation of mu-delta opioid receptor (OR) heterooligomers were studied. Bioluminescence resonance energy transfer (BRET) showed that mu-deltaOR heterooligomers, composed of preformed mu and delta homooligomers, interacted constitutively in the endoplasmic reticulum (ER) with Galpha-proteins forming heteromeric signaling complexes before being targeted to the plasma membrane. Compared to muOR homooligomers, the mu-delta heterooligomers showed higher affinity and efficiency of interaction for Gz over Gi, indicating a switch in G-protein preference. Treatment with DAMGO or deltorphin II led to coregulated internalization of both receptors, whereas DPDPE and DSLET had no effect on mu-delta internalization. Staggered expression resulted in non-interacting mu and delta receptors, even though both receptors were colocalized at the cell surface. Agonists failed to induce BRET between staggered receptors, and resulted in internalization solely of the receptor targeted by agonist. Thus, mu-deltaOR heterooligomers form and preferentially associate with Gz to generate a signaling complex in the ER, and have a distinct agonist-internalization profile compared to either mu or delta homooligomers.
authors.affiliation: The Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hasbi
authors.forename: Tuan
authors.initials: T
authors.lastname: Nguyen
authors.forename: Theresa
authors.initials: T
authors.lastname: Fan
authors.forename: Regina
authors.initials: R
authors.lastname: Cheng
authors.forename: Asim
authors.initials: A
authors.lastname: Rashid
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alijaniaram
authors.forename: Mark M
authors.initials: MM
authors.lastname: Rasenick
authors.forename: Brian F
authors.initials: BF
authors.lastname: O'Dowd
authors.forename: Susan R
authors.initials: SR
authors.lastname: George
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects*; D002478:Cells, Cultured; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D021381:Protein Transport; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060209:deltorphin II, Ala(2)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D019204:GTP-Binding Proteins