In Vitro Analyses of Spinach-Derived Opioid Peptides, Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and β-Arrestin-Mediated Pathways
| Autor: | Akane Komatsu, Takaaki Mizuguchi, Hideaki Fujii, Yasuhito Uezono, Keisuke Yamaguchi, Kaori Ohshima, Masahiro Yamaguchi, Yusuke Karasawa, Yui Kuroda, Kanako Miyano, Miki Nonaka, Masako Iseki, Masakazu Hayashida |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
G protein
medicine.drug_class Ribulose-Bisphosphate Carboxylase Analgesic Heteromer Receptors Opioid mu Pharmaceutical Science G-protein-biased agonist Pharmacology Article Analytical Chemistry QD241-441 Opioid receptor GTP-Binding Proteins Spinacia oleracea Receptors Opioid delta Drug Discovery opioid peptide medicine Arrestin Humans δ opioid receptor Physical and Theoretical Chemistry Opioid peptide Receptor beta-Arrestins Molecular Structure Chemistry Organic Chemistry analgesic Peptide Fragments HEK293 Cells Opioid Gene Expression Regulation Opioid Peptides Chemistry (miscellaneous) Molecular Medicine rubiscolins medicine.drug Signal Transduction |
| Zdroj: | Molecules Volume 26 Issue 19 Molecules, Vol 26, Iss 6079, p 6079 (2021) |
| ISSN: | 1420-3049 |
| Popis: | Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKeyTM assay, cADDis® cAMP assay, and PathHunter® β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKeyTM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis® cAMP and PathHunter® β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects. |
| Databáze: | OpenAIRE |
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