{"doi":"10.1101/2024.10.07.617095","title":"Opioid receptors reveal a discrete cellular mechanism of endosomal G protein activation","abstract":"Abstract Many GPCRs initiate a second phase of G protein-mediated signaling from endosomes, which inherently requires an increase in G protein activity on the endosome surface. G s -coupled GPCRs are thought to achieve this by internalizing and allosterically activating cognate G proteins again on the endosome membrane. Here we demonstrate that the μ-opioid receptor (MOR), a G i -coupled GPCR, increases endosomal G protein activity in a different way. Leveraging conformational biosensors, we resolve the subcellular activation dynamics of endogenously expressed MOR and G i/o -subclass G proteins. We show that MOR activation triggers a transient increase of active-state G i/o on the plasma membrane that is followed by a prolonged increase on endosomes. Contrary to the G s -coupled GPCR paradigm, however, we show that the MOR-induced increase of active-state G i/o on endosomes requires neither internalization of MOR nor activation of MOR in the endosome membrane. We propose a distinct and additional cellular mechanism for GPCR-triggered elevation of G protein activity on endosomes that is mediated by regulated trafficking of the activated G protein rather than its activating GPCR.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486402,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320027,"name":"Mark von Zastrow","orcid":"0000-0003-1375-6926","position":1,"is_corresponding":false},{"id":695344,"name":"Nicole M. Fisher","orcid":"0000-0001-6740-9618","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:01.404471Z","pmid":"39416059","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":[]}