Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity

Kirchhofer, Sina B; Lim, Victor Jun Yu; Ernst, Sebastian; Karsai, Noemi; Julia, Ruland G; Canals, Meritxell; Kolb, Peter; Bünemann, Moritz

Abstract

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.

Citation

Kirchhofer, S. B., Lim, V. J. Y., Ernst, S., Karsai, N., Julia, R. G., Canals, M., …Bünemann, M. (2023). Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity. eLife, 12, Article e91291. https://doi.org/10.7554/eLife.91291

• Journal Article Type: Article
• Acceptance Date: Nov 19, 2023
• Online Publication Date: Nov 20, 2023
• Publication Date: Nov 20, 2023
• Deposit Date: Feb 5, 2024
• Publicly Available Date: Feb 8, 2024
• Journal: eLife
• Electronic ISSN: 2050-084X
• Publisher: eLife Sciences Publications
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Article Number: e91291
• DOI: https://doi.org/10.7554/eLife.91291
• Keywords: Neuroscience; voltage; GPCR; ligands; opioid; Förster resonance energy transfer; binding mode
• Public URL: https://nottingham-repository.worktribe.com/output/28134248
• Publisher URL: https://elifesciences.org/articles/91291
• Additional Information: Peer review transparency: single anonymised; Peer review interaction: other reviewer(s), editor; Peer review published: review summaries, review reports, author/editor communication, reviewer identities reviewer opt in, editor identities; Post publication commenting: open (sign in with ORCID iD required)