The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules

Laura Lemel, Katarzyna Nieścierowicz, M. Dolores García-fernández, Leonardo Darré, Thierry Durroux, Marta Busnelli, Mylène Pezet, Fabrice Rebeille, Juliette Jouhet, Bernard Mouillac, Carmen Domene, Bice Chini, Vadim Cherezov, Christophe J. Moreau

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11 Citations (SciVal)


Cholesterol is a major component of mammalian plasma membranes that not only affects the physical properties of the lipid bilayer but also is the function of many membrane proteins including G protein-coupled receptors. The oxytocin receptor (OXTR) is involved in parturition and lactation of mammals and in their emotional and social behaviors. Cholesterol acts on OXTR as an allosteric modulator inducing a high-affinity state for orthosteric ligands through a molecular mechanism that has yet to be determined. Using the ion channel-coupled receptor technology, we developed a functional assay of cholesterol modulation of G protein-coupled receptors that is independent of intracellular signaling pathways and operational in living cells. Using this assay, we discovered a stable binding of cholesterol molecules to the receptor when it adopts an orthosteric ligand-bound state. This stable interaction preserves the cholesterol-dependent activity of the receptor in cholesterol-depleted membranes. This mechanism was confirmed using time-resolved FRET experiments on WT OXTR expressed in CHO cells. Consequently, a positive cross-regulation sequentially occurs in OXTR between cholesterol and orthosteric ligands.
Original languageEnglish
Article number100059
JournalJournal of Lipid Research
Early online date26 Feb 2021
Publication statusPublished - 31 Dec 2021


  • Allosteric regulation
  • Cholesterol
  • Cholesterol binding
  • Cholesterol/physical chemistry
  • Lipid rafts
  • Membrane protein-lipid interaction
  • Molecular biology
  • Oxytocin G protein-coupled receptor
  • Receptors/plasma membrane
  • Receptors/seven transmembrane domain

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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