Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist
The prevailing model for the variety in drug responses is that different drugs stabilize distinct active states of their G protein-coupled receptor (GPCR) targets, allowing coupling to different effectors. However, whether the same ligand generates different GPCR active states based on the immediate...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67478 |
| _version_ | 1811236749804830720 |
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| author | Stephanie E Crilly Wooree Ko Zara Y Weinberg Manojkumar A Puthenveedu |
| author_facet | Stephanie E Crilly Wooree Ko Zara Y Weinberg Manojkumar A Puthenveedu |
| author_sort | Stephanie E Crilly |
| collection | DOAJ |
| description | The prevailing model for the variety in drug responses is that different drugs stabilize distinct active states of their G protein-coupled receptor (GPCR) targets, allowing coupling to different effectors. However, whether the same ligand generates different GPCR active states based on the immediate environment of receptors is not known. Here we address this question using spatially resolved imaging of conformational biosensors that read out distinct active conformations of the δ-opioid receptor (DOR), a physiologically relevant GPCR localized to Golgi and the surface in neuronal cells. We have shown that Golgi and surface pools of DOR both inhibit cAMP, but engage distinct conformational biosensors in response to the same ligand in rat neuroendocrine cells. Further, DOR recruits arrestins on the surface but not on the Golgi. Our results suggest that the local environment determines the active states of receptors for any given drug, allowing GPCRs to couple to different effectors at different subcellular locations. |
| first_indexed | 2024-04-12T12:14:33Z |
| format | Article |
| id | doaj.art-66e06d8ec03a497d93f59280819150ea |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:14:33Z |
| publishDate | 2021-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-66e06d8ec03a497d93f59280819150ea2022-12-22T03:33:29ZengeLife Sciences Publications LtdeLife2050-084X2021-05-011010.7554/eLife.67478Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonistStephanie E Crilly0https://orcid.org/0000-0002-8151-290XWooree Ko1Zara Y Weinberg2https://orcid.org/0000-0001-7176-038XManojkumar A Puthenveedu3https://orcid.org/0000-0002-3177-4231Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States; Department of Pharmacology University of Michigan Medical School, Ann Arbor, United StatesDepartment of Pharmacology University of Michigan Medical School, Ann Arbor, United StatesDepartment of Pharmacology University of Michigan Medical School, Ann Arbor, United StatesCellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States; Department of Pharmacology University of Michigan Medical School, Ann Arbor, United StatesThe prevailing model for the variety in drug responses is that different drugs stabilize distinct active states of their G protein-coupled receptor (GPCR) targets, allowing coupling to different effectors. However, whether the same ligand generates different GPCR active states based on the immediate environment of receptors is not known. Here we address this question using spatially resolved imaging of conformational biosensors that read out distinct active conformations of the δ-opioid receptor (DOR), a physiologically relevant GPCR localized to Golgi and the surface in neuronal cells. We have shown that Golgi and surface pools of DOR both inhibit cAMP, but engage distinct conformational biosensors in response to the same ligand in rat neuroendocrine cells. Further, DOR recruits arrestins on the surface but not on the Golgi. Our results suggest that the local environment determines the active states of receptors for any given drug, allowing GPCRs to couple to different effectors at different subcellular locations.https://elifesciences.org/articles/67478GPCRspatial encodingsignalingorganelle |
| spellingShingle | Stephanie E Crilly Wooree Ko Zara Y Weinberg Manojkumar A Puthenveedu Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist eLife GPCR spatial encoding signaling organelle |
| title | Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist |
| title_full | Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist |
| title_fullStr | Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist |
| title_full_unstemmed | Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist |
| title_short | Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist |
| title_sort | conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist |
| topic | GPCR spatial encoding signaling organelle |
| url | https://elifesciences.org/articles/67478 |
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