{"doi":"10.1124/mol.116.106633","title":"Sequence-Specific Regulation of Endocytic Lifetimes Modulates Arrestin-Mediated Signaling at the µ Opioid Receptor","abstract":null,"journal":"Molecular Pharmacology","year":2017,"id":626220,"datarank":0.48283137373023016,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"self_citation_contribution":0.48283137373023016,"citation_network_contribution":0.0,"self_endowment_contribution":0.48283137373023016,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":551752,"name":"Amanda S. Zajac","orcid":"0000-0003-0180-0950","position":1,"is_corresponding":false},{"id":1619819,"name":"Tiffany Phan","orcid":null,"position":2,"is_corresponding":false},{"id":281075,"name":"Daniel J. Shiwarski","orcid":"0000-0001-6978-303X","position":3,"is_corresponding":false},{"id":262336,"name":"Manojkumar A. Puthenveedu","orcid":"0000-0002-3177-4231","position":4,"is_corresponding":false},{"id":88662,"name":"Zara Y. Weinberg","orcid":"0000-0001-7176-038X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Sequence-Specific Regulation of Endocytic Lifetimes Modulates Arrestin-Mediated Signaling at the µ Opioid Receptor","abstract":"Functional selectivity at the <i>µ</i> opioid receptor (<i>µ</i>R), a prototypical G-protein-coupled receptor that is a physiologically relevant target for endogenous opioid neurotransmitters and analgesics, has been a major focus for drug discovery in the recent past. Functional selectivity is a cumulative effect of the magnitudes of individual signaling pathways, e.g., the G<i>α</i><sub>i</sub>-mediated and the arrestin-mediated pathways for <i>µ</i>R. The present work tested the hypothesis that lifetimes of agonist-induced receptor-arrestin clusters at the cell surface control the magnitude of arrestin signaling, and therefore functional selectivity, at <i>µ</i>R. We show that endomorphin-2 (EM2), an arrestin-biased ligand for <i>µ</i>R, lengthens surface lifetimes of receptor-arrestin clusters significantly compared with morphine. The lengthening of lifetimes required two specific leucines on the C-terminal tail of <i>µ</i>R. Mutation of these leucines to alanines decreased the magnitude of arrestin-mediated signaling by EM2 without affecting G-protein signaling, suggesting that lengthened endocytic lifetimes were required for arrestin-biased signaling by EM2. Lengthening surface lifetimes by pharmacologically slowing endocytosis was sufficient to increase arrestin-mediated signaling by both EM2 and the clinically relevant agonist morphine. Our findings show that distinct ligands can leverage specific sequence elements on <i>µ</i>R to regulate receptor endocytic lifetimes and the magnitude of arrestin-mediated signaling, and implicate these sequences as important determinants of functional selectivity in the opioid system.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28153854","pmcid":"PMC5363713","openalex_id":null,"authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM117425","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R00 DA024698","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"K99 DA024698","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"T32 NS007433","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R21 DA036086","title":null}],"total_grants":5,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"bronze","license":"https://www.elsevier.com/legal/tdmrep-license","oa_locations":[{"url":"https://molpharm.aspetjournals.org/content/molpharm/91/4/416.full.pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0026895X24005832?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0026895X24005832?httpAccept=text/plain","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1124/mol.116.106633","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5363713","host_type":"repository"}],"fields_of_study":[],"mesh_terms":["Humans","Morphine","Extracellular Signal-Regulated MAP Kinases","Oligopeptides","Receptors, Opioid, mu","Signal Transduction","Endocytosis","MAP Kinase Signaling System","Enzyme Activation","Amino Acid Sequence","Mutation","Time Factors","HEK293 Cells","beta-Arrestins"],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T12:56:47.406041Z","pmid":null,"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":[]}