Single-molecule analysis reveals agonist-specific dimer formation of µ-opioid receptors

Jan Möller, Ali Isbilir, Titiwat Sungkaworn, Brendan Osberg, Christos Karathanasis, Vikram Sunkara, Eugene O Grushevskyi, Andreas Bock, Paolo Annibale, Mike Heilemann, Christof Schütte, Martin J Lohse

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

Abstract

G-protein-coupled receptors (GPCRs) are key signaling proteins that mostly function as monomers, but for several receptors constitutive dimer formation has been described and in some cases is essential for function. Using single-molecule microscopy combined with super-resolution techniques on intact cells, we describe here a dynamic monomer-dimer equilibrium of µ-opioid receptors (µORs), where dimer formation is driven by specific agonists. The agonist DAMGO, but not morphine, induces dimer formation in a process that correlates both temporally and in its agonist- and phosphorylation-dependence with β-arrestin2 binding to the receptors. This dimerization is independent from, but may precede, µOR internalization. These data suggest a new level of GPCR regulation that links dimer formation to specific agonists and their downstream signals.

Original languageEnglish
Pages (from-to)946-954
Number of pages9
JournalNature Chemical Biology
Volume16
Issue number9
Early online date15 Jun 2020
DOIs
Publication statusPublished - Sept 2020

Keywords

  • Animals
  • CHO Cells
  • Cricetulus
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/chemistry
  • Fluorescence Resonance Energy Transfer
  • Morphine/chemistry
  • Mutation
  • Naloxone/chemistry
  • Naltrexone/analogs & derivatives
  • Narcotic Antagonists/chemistry
  • Phosphorylation
  • Protein Multimerization
  • Receptors, Opioid, mu/agonists
  • Single Molecule Imaging/methods
  • beta-Arrestins/metabolism

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