Biased μ-opioid receptor agonists diversely regulate lateral mobility and functional coupling of the receptor to its cognate G proteins
Language English Country Germany Media print-electronic
Document type Comparative Study, Journal Article
PubMed
27600870
DOI
10.1007/s00210-016-1293-8
PII: 10.1007/s00210-016-1293-8
Knihovny.cz E-resources
- Keywords
- Biased agonists *, Cholesterol *, FRAP *, G protein coupling *, μ-Opioid receptor *,
- MeSH
- Bacterial Proteins genetics metabolism MeSH
- Cell Membrane drug effects metabolism MeSH
- Cholesterol deficiency MeSH
- Enkephalin, Ala(2)-MePhe(4)-Gly(5)- metabolism pharmacology MeSH
- Fluorescence Recovery After Photobleaching MeSH
- Guanosine 5'-O-(3-Thiotriphosphate) metabolism MeSH
- HEK293 Cells MeSH
- Microscopy, Confocal MeSH
- Humans MeSH
- Ligands MeSH
- Luminescent Proteins genetics metabolism MeSH
- Morphine metabolism pharmacology MeSH
- Narcotic Antagonists pharmacology MeSH
- Oligopeptides metabolism pharmacology MeSH
- Pertussis Toxin pharmacology MeSH
- GTP-Binding Protein alpha Subunits, Gi-Go metabolism MeSH
- Receptors, Opioid, mu agonists genetics metabolism MeSH
- Recombinant Fusion Proteins metabolism MeSH
- Transfection MeSH
- Protein Transport MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
- Names of Substances
- Bacterial Proteins MeSH
- Cholesterol MeSH
- endomorphin 2 MeSH Browser
- Enkephalin, Ala(2)-MePhe(4)-Gly(5)- MeSH
- Guanosine 5'-O-(3-Thiotriphosphate) MeSH
- Ligands MeSH
- Luminescent Proteins MeSH
- Morphine MeSH
- Narcotic Antagonists MeSH
- Oligopeptides MeSH
- Pertussis Toxin MeSH
- GTP-Binding Protein alpha Subunits, Gi-Go MeSH
- Receptors, Opioid, mu MeSH
- Recombinant Fusion Proteins MeSH
- yellow fluorescent protein, Bacteria MeSH Browser
There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala2,N-MePhe4,Gly5-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2. Interestingly, cholesterol depletion strongly enhanced the ability of morphine to elevate receptor mobility but significantly reduced or even eliminated the effect of DAMGO and endomorphin-2, respectively. Moreover, the ability of DAMGO and endomorphin-2 to influence MOR-YFP movement was diminished by pertussis toxin treatment. The results obtained by agonist-stimulated [35S]GTPγS binding assays indicated that DAMGO exhibited higher efficacy than morphine and endomorphin-2 did and that the efficacy of DAMGO, contrary to the latter agonists, was enhanced by cholesterol depletion. Overall, our study provides clear evidence that biased MOR agonists diversely affect receptor mobility in plasma membranes as well as MOR/G protein coupling and that the regulatory effect of different ligands depends on the membrane cholesterol content. These findings help to delineate the fundamental properties of MOR regarding their interaction with biased MOR ligands and cognate G proteins.
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