{"doi":"10.1101/2025.07.04.663222","title":"Cytoplasmic tail composition modulates the G protein and arrestin-3 signaling bias of the adhesion GPCR LPHN2","abstract":"The class B2 Adhesion GPCRs (aGPCRs) combine cell adhesion with GPCR signaling to control diverse developmental and physiological processes. How aGPCRs interact with and integrate distinct groups of effectors including G proteins, arrestins, and G protein receptor kinases (GRKs) remains unclear. Here, we find that diversity in the aGPCR C-terminal intracellular tail modulates G protein activation, arrestin-3 recruitment, and utilization of selective GRKs in LPHN2, a postsynaptic aGPCR essential for synapse formation. The C-terminal tail of LPHN2 is required for G protein activation and arrestin-3 recruitment. LPHN2 with an intact tail recruits arrestin-3 in the absence of G protein activation, suggesting constitutive arrestin-3-biased signaling. Alternative splicing of the LPHN2 tail modulates G protein activation and arrestin-3 binding independently, supporting that it controls G protein vs arrestin-3 bias. GRKs are important but not essential for arrestin-3 recruitment to LPHN2. Moreover, GRK2 increases arrestin-3 recruitment only in a subset of LPHN2 variants. Collectively, these results show that the mechanisms of the interactions of class B2 aGPCRs and arrestin are distinct from those of class A GPCRs and that splicing of the LPHN2 C-terminal tail determines G protein vs arrestin bias.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556524,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":395410,"name":"Chen Zheng","orcid":"0000-0002-3610-5715","position":1,"is_corresponding":false},{"id":1047653,"name":"Julia Drube","orcid":"0000-0001-6188-2279","position":2,"is_corresponding":false},{"id":578790,"name":"Carsten Hoffmann","orcid":"0000-0003-0884-9300","position":3,"is_corresponding":false},{"id":271822,"name":"Vsevolod V. Gurevich","orcid":"0000-0002-3950-5351","position":4,"is_corresponding":false},{"id":720343,"name":"Richard Sando","orcid":"0000-0002-1797-2346","position":5,"is_corresponding":false},{"id":1325899,"name":"Krassimira Garbett","orcid":"0000-0003-3969-3919","position":0,"is_corresponding":true}],"reference_count":1,"raw_metadata":null,"created_at":"2026-07-19T02:55:08.896385Z","pmid":"40631154","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":[]}