{"doi":"10.1124/molpharm.124.000942","title":"Receptor Determinants for β-Arrestin Functional Specificity at C-X-C Chemokine Receptor 5","abstract":"β -arrestins are multifaceted adaptor proteins that mediate G protein-coupled receptor (GPCR) desensitization, internalization, and signaling. It is emerging that receptor-specific determinants specify these divergent functions at GPCRs, yet this remains poorly understood. Here, we set out to identify the receptor determinants responsible for β -arrestin-mediated regulation of the chemokine receptor C-X-C motif chemokine receptor 5 (CXCR5). Using bioluminescence resonance energy transfer, we show that β -arrestin1 and β -arrestin2 are dose-dependently recruited to CXCR5 by its cognate ligand C-X-C motif chemokine ligand 13 (CXCL13). The carboxy-terminal tail of CXCR5 contains several serine/threonine residues that can be divided into three discrete phospho-site clusters based on their position relative to transmembrane domain 7. Mutagenesis experiments revealed that the distal and medial phospho-site clusters, but not the proximal, are required for agonist-stimulated β -arrestin1 or β -arrestin2 recruitment to CXCR5. Consistent with this, we provide evidence that the distal and medial, but not proximal, phospho-site clusters are required for receptor desensitization. Surprisingly, the individual phospho-site clusters are not required for agonist-stimulated internalization of CXCR5. Further, we show that CXCL13-stimulated CXCR5 internalization and ERK1/2 phosphorylation, but not desensitization, remain intact in human embryonic kidney 293 cells lacking β -arrestin1 and β -arrestin2. Our study provides evidence that β -arrestins are recruited to CXCR5 and are required for desensitization but are dispensable for internalization or signaling, suggesting that discrete receptor determinants specify the divergent functions of β -arrestins. SIGNIFICANCE STATEMENT C-X-C motif ligand 13 (CXCL13) and C-X-C motif chemokine receptor 5 (CXCR5) are important in the immune system and are linked to diseases, yet regulation of CXCR5 signaling remains poorly understood. We provide evidence that a phospho-site cluster located at the extreme distal carboxyl-terminal tail of the receptor is responsible for β -arrestin recruitment and receptor desensitization. β -arrestins are not required for CXCL13-stimulated internalization or signaling, indicating that β -arrestins perform only one of their functions at CXCR5 and that discrete receptor determinants specify the divergent functions of β -arrestins.","journal":"Molecular Pharmacology","year":2024,"id":447752,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"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":1266385,"name":"Aaren R Manz","orcid":null,"position":1,"is_corresponding":false},{"id":1139368,"name":"Sara Benzow","orcid":null,"position":2,"is_corresponding":false},{"id":370582,"name":"Adriano Marchese","orcid":null,"position":3,"is_corresponding":false},{"id":905914,"name":"Joseph M. Crecelius","orcid":"0000-0003-2370-9154","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:02:03.354708Z","pmid":"39472027","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":[]}