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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208814/ https://www.ncbi.nlm.nih.gov/pubmed/34013886 http://dx.doi.org/10.7554/eLife.67478 |
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author | Crilly, Stephanie E Ko, Wooree Weinberg, Zara Y Puthenveedu, Manojkumar A |
author_facet | Crilly, Stephanie E Ko, Wooree Weinberg, Zara Y Puthenveedu, Manojkumar A |
author_sort | Crilly, Stephanie E |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-8208814 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-82088142021-06-21 Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist Crilly, Stephanie E Ko, Wooree Weinberg, Zara Y Puthenveedu, Manojkumar A eLife Cell Biology 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. eLife Sciences Publications, Ltd 2021-05-20 /pmc/articles/PMC8208814/ /pubmed/34013886 http://dx.doi.org/10.7554/eLife.67478 Text en © 2021, Crilly et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Crilly, Stephanie E Ko, Wooree Weinberg, Zara Y Puthenveedu, Manojkumar A Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist |
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 | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208814/ https://www.ncbi.nlm.nih.gov/pubmed/34013886 http://dx.doi.org/10.7554/eLife.67478 |
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