Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity
The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activation and subsequent effects. A better understanding o...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/91291 |
| _version_ | 1797321524599848960 |
|---|---|
| author | Sina B Kirchhofer Victor Jun Yu Lim Sebastian Ernst Noemi Karsai Julia G Ruland Meritxell Canals Peter Kolb Moritz Bünemann |
| author_facet | Sina B Kirchhofer Victor Jun Yu Lim Sebastian Ernst Noemi Karsai Julia G Ruland Meritxell Canals Peter Kolb Moritz Bünemann |
| author_sort | Sina B Kirchhofer |
| collection | DOAJ |
| description | The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activation and subsequent effects. A better understanding of ligand-receptor interactions and the resulting effects is important. Here, we calculated the respective binding poses for several opioids and analyzed interaction fingerprints between ligand and receptor. We further corroborated the interactions experimentally by cellular assays. As MOR was observed to display ligand-induced modulation of activity due to changes in membrane potential, we further analyzed the effects of voltage sensitivity on this receptor. Combining in silico and in vitro approaches, we defined discriminating interaction patterns responsible for ligand-specific voltage sensitivity and present new insights into their specific effects on activation of the MOR. |
| first_indexed | 2024-03-08T04:59:49Z |
| format | Article |
| id | doaj.art-d5eb377bbd5c46ab8998c51de514679a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T04:59:49Z |
| publishDate | 2023-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d5eb377bbd5c46ab8998c51de514679a2024-02-07T13:15:57ZengeLife Sciences Publications LtdeLife2050-084X2023-11-011210.7554/eLife.91291Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivitySina B Kirchhofer0https://orcid.org/0000-0001-6285-9054Victor Jun Yu Lim1Sebastian Ernst2Noemi Karsai3https://orcid.org/0009-0000-3948-4071Julia G Ruland4Meritxell Canals5Peter Kolb6https://orcid.org/0000-0003-4089-614XMoritz Bünemann7https://orcid.org/0000-0002-2259-4378Department of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands, United KingdomDepartment of Pharmaceutical Chemistry, University of Marburg, Marburg, GermanyDepartment of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, GermanyDivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands, United KingdomDepartment of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, GermanyDivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands, United KingdomDepartment of Pharmaceutical Chemistry, University of Marburg, Marburg, GermanyDepartment of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, GermanyThe µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activation and subsequent effects. A better understanding of ligand-receptor interactions and the resulting effects is important. Here, we calculated the respective binding poses for several opioids and analyzed interaction fingerprints between ligand and receptor. We further corroborated the interactions experimentally by cellular assays. As MOR was observed to display ligand-induced modulation of activity due to changes in membrane potential, we further analyzed the effects of voltage sensitivity on this receptor. Combining in silico and in vitro approaches, we defined discriminating interaction patterns responsible for ligand-specific voltage sensitivity and present new insights into their specific effects on activation of the MOR.https://elifesciences.org/articles/91291voltageGPCRligandsopioidFörster resonance energy transferbinding mode |
| spellingShingle | Sina B Kirchhofer Victor Jun Yu Lim Sebastian Ernst Noemi Karsai Julia G Ruland Meritxell Canals Peter Kolb Moritz Bünemann Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity eLife voltage GPCR ligands opioid Förster resonance energy transfer binding mode |
| title | Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity |
| title_full | Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity |
| title_fullStr | Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity |
| title_full_unstemmed | Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity |
| title_short | Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity |
| title_sort | differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand specific voltage sensitivity |
| topic | voltage GPCR ligands opioid Förster resonance energy transfer binding mode |
| url | https://elifesciences.org/articles/91291 |
| work_keys_str_mv | AT sinabkirchhofer differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity AT victorjunyulim differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity AT sebastianernst differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity AT noemikarsai differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity AT juliagruland differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity AT meritxellcanals differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity AT peterkolb differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity AT moritzbunemann differentialinteractionpatternsofopioidanalgesicswithμopioidreceptorscorrelatewithligandspecificvoltagesensitivity |