TY - JOUR
T1 - Single-molecule analysis reveals agonist-specific dimer formation of µ-opioid receptors
AU - Möller, Jan
AU - Isbilir, Ali
AU - Sungkaworn, Titiwat
AU - Osberg, Brendan
AU - Karathanasis, Christos
AU - Sunkara, Vikram
AU - Grushevskyi, Eugene O
AU - Bock, Andreas
AU - Annibale, Paolo
AU - Heilemann, Mike
AU - Schütte, Christof
AU - Lohse, Martin J
N1 - Funding: This work was supported by the Deutsche Forschungsgemeinschaft, TR166 (to M.J.L.), the National Institutes of Health grant DA038882 (to M.J.L.), the cluster of excellence MATH+ (to C.S. and M.J.L.) and the Elitenetzwerk Bayern, Receptor Dynamics program (to M.J.L.). B.O. received funding by the EU Horizon 2020 research and innovation program, CORBEL, grant no. 654248.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - Animals
KW - CHO cells
KW - Cricetulus
KW - Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/chemistry
KW - Fluorescence resonance energy transfer
KW - Morphine/chemistry
KW - Mutation
KW - Naloxone/chemistry
KW - Naltrexone/analogs & derivatives
KW - Narcotic antagonists/chemistry
KW - Phosphorylation
KW - Protein multimerization
KW - Receptors, opioid, mu/agonists
KW - Single molecule imaging/methods
KW - Beta-arrestins/metabolism
U2 - 10.1038/s41589-020-0566-1
DO - 10.1038/s41589-020-0566-1
M3 - Article
C2 - 32541966
SN - 1552-4450
VL - 16
SP - 946
EP - 954
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 9
ER -