Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor
Abstract The endogenous opioid system provides powerful control over emotions, nociception, and motivation among many other fundamental nervous system functions. Its major components include a panel of opioid peptides that activate four canonical inhibitory opioid receptors. However, its regulatory...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62133-x |
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| author | Xiaona Li Nathan D. Winters Shubhi Pandey Colten Lankford Hannah M. Stoveken Emery Smith Chu-Ting Chang Stefano Zucca Louis Scampavia Timothy Spicer Kirill A. Martemyanov |
| author_facet | Xiaona Li Nathan D. Winters Shubhi Pandey Colten Lankford Hannah M. Stoveken Emery Smith Chu-Ting Chang Stefano Zucca Louis Scampavia Timothy Spicer Kirill A. Martemyanov |
| author_sort | Xiaona Li |
| collection | DOAJ |
| description | Abstract The endogenous opioid system provides powerful control over emotions, nociception, and motivation among many other fundamental nervous system functions. Its major components include a panel of opioid peptides that activate four canonical inhibitory opioid receptors. However, its regulatory principles are not fully understood including the existence of additional receptors and other elements. In this study we report the identification of a receptor for the opioid peptide dynorphin. By conducting a screen of a custom library of neuropeptides, we found that orphan receptor GPR139 binds to and is activated by a series of dynorphin peptides. Unlike other opioid receptors, GPR139 couples to Gq/11 and avoids β-arrestin, providing excitatory signaling that homeostatically scales the inhibitory response of neurons to dynorphin. This introduces a non-canonical dynorphin receptor as an essential component of the opioid system. |
| format | Article |
| id | doaj-art-d9cd21f897d6444c90f12f36fc271386 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d9cd21f897d6444c90f12f36fc2713862025-08-20T03:43:14ZengNature PortfolioNature Communications2041-17232025-07-0116111610.1038/s41467-025-62133-xHomeostatic scaling of dynorphin signaling by a non-canonical opioid receptorXiaona Li0Nathan D. Winters1Shubhi Pandey2Colten Lankford3Hannah M. Stoveken4Emery Smith5Chu-Ting Chang6Stefano Zucca7Louis Scampavia8Timothy Spicer9Kirill A. Martemyanov10Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyDepartment of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & TechnologyAbstract The endogenous opioid system provides powerful control over emotions, nociception, and motivation among many other fundamental nervous system functions. Its major components include a panel of opioid peptides that activate four canonical inhibitory opioid receptors. However, its regulatory principles are not fully understood including the existence of additional receptors and other elements. In this study we report the identification of a receptor for the opioid peptide dynorphin. By conducting a screen of a custom library of neuropeptides, we found that orphan receptor GPR139 binds to and is activated by a series of dynorphin peptides. Unlike other opioid receptors, GPR139 couples to Gq/11 and avoids β-arrestin, providing excitatory signaling that homeostatically scales the inhibitory response of neurons to dynorphin. This introduces a non-canonical dynorphin receptor as an essential component of the opioid system.https://doi.org/10.1038/s41467-025-62133-x |
| spellingShingle | Xiaona Li Nathan D. Winters Shubhi Pandey Colten Lankford Hannah M. Stoveken Emery Smith Chu-Ting Chang Stefano Zucca Louis Scampavia Timothy Spicer Kirill A. Martemyanov Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor Nature Communications |
| title | Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor |
| title_full | Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor |
| title_fullStr | Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor |
| title_full_unstemmed | Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor |
| title_short | Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor |
| title_sort | homeostatic scaling of dynorphin signaling by a non canonical opioid receptor |
| url | https://doi.org/10.1038/s41467-025-62133-x |
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