{"doi":"10.1016/j.jlr.2021.100059","title":"The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules","abstract":"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.","journal":"Journal of Lipid Research","year":2021,"id":174209,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":713172,"name":"Katarzyna Nieścierowicz","orcid":"0000-0001-9908-9516","position":1,"is_corresponding":false},{"id":713173,"name":"M. Dolores García-Fernández","orcid":"0000-0001-6519-7594","position":2,"is_corresponding":false},{"id":713174,"name":"Leonardo Darré","orcid":"0000-0001-5280-8579","position":3,"is_corresponding":false},{"id":713175,"name":"Thierry Durroux","orcid":"0000-0003-1091-6066","position":4,"is_corresponding":false},{"id":713176,"name":"Marta Busnelli","orcid":"0000-0003-3387-2190","position":5,"is_corresponding":false},{"id":713177,"name":"Mylène Pezet","orcid":"0000-0002-4365-7454","position":6,"is_corresponding":false},{"id":713178,"name":"Fabrice Rébeillé","orcid":"0000-0001-6132-8542","position":7,"is_corresponding":false},{"id":713179,"name":"Juliette Jouhet","orcid":"0000-0002-4402-2194","position":8,"is_corresponding":false},{"id":713180,"name":"Bernard Mouillac","orcid":"0000-0002-3906-8673","position":9,"is_corresponding":false},{"id":713181,"name":"Cármen Domene","orcid":"0000-0001-7115-4232","position":10,"is_corresponding":false},{"id":713182,"name":"Bice Chini","orcid":"0000-0002-1686-284X","position":11,"is_corresponding":false},{"id":198890,"name":"Vadim Cherezov","orcid":"0000-0002-5265-3914","position":12,"is_corresponding":false},{"id":713183,"name":"Christophe Moreau","orcid":"0000-0002-5463-9593","position":13,"is_corresponding":false},{"id":713171,"name":"Laura Lemel","orcid":"0000-0002-6263-1735","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-18T23:46:54.772014Z","pmid":"33647276","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}