title: Differential response to morphine of the oligomeric state of μ-opioid in the presence of δ-opioid receptors.
abstract: Prolonged morphine treatment induces extensive desensitization of the μ-opioid receptor (μOR) which is the G-protein-coupled receptor that primarily mediates the cellular response to morphine. To date, the molecular mechanism underlying this process is unknown. Here, we have used live cell fluorescence imaging to investigate whether prolonged morphine treatment affects the physical environment of μOR, or its coupling with G-proteins, in two neuronal cell lines. We find that chronic morphine treatment does not change the amount of enhanced yellow fluorescence protein (eYFP)-tagged μOR on the plasma membrane, and only slightly decreases its association with G-protein subunits. Additionally, morphine treatment does not have a detectable effect on the diffusion coefficient of eYFP-μOR. However, in the presence of another family member, the δ-opioid receptor (δOR), prolonged morphine exposure results in a significant increase in the diffusion rate of μOR. Number and brightness measurements suggest that μOR exists primarily as a dimer that will oligomerize with δOR into tetramers, and morphine promotes the dissociation of these tetramers. To provide a plausible structural context to these data, we used homology modeling techniques to generate putative configurations of μOR-δOR tetramers. Overall, our studies provide a possible rationale for morphine sensitivity.
authors.affiliation: Department of Biological Sciences and Geology, Queensboro Community College, Bayside, New York 11364-1497, United States.
authors.forename: Urszula
authors.initials: U
authors.lastname: Golebiewska
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Johnston
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Devi
authors.forename: Marta
authors.initials: M
authors.lastname: Filizola
authors.forename: Suzanne
authors.initials: S
authors.lastname: Scarlata
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009020:Morphine / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D008164:Luminescent Proteins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009020:Morphine