{"doi":"10.1371/journal.pone.0315820","title":"TAS2R5 screening reveals biased agonism that fails to evoke internalization and downregulation resulting in attenuated desensitization","abstract":"The bitter taste receptor type 5 (TAS2R5) is expressed on multiple cell types and appears to be a suitable target for novel agonist treatments across multiple therapeutic areas. Like most G protein coupled receptors (GPCRs), TAS2R5 undergoes functional desensitization with prolonged agonist exposure which could limit effectiveness. The net loss of cellular receptors (termed downregulation) is a prominent mechanism of long-term desensitization; we screened 13 agonists for downregulation of receptor protein in TAS2R5-transfected HEK-293T and airway smooth muscle cells in culture, searching for pathway selectivity favoring G protein coupling over downregulation. The benchmark agonist 1,10-phenanthroline (denoted T5-1) evoked as much as 75% downregulation of TAS2R5 protein expression with 18-24 hrs of agonist exposure, while an analogue of T5-1 (denoted T5-12) caused a 2-3 fold increase in expression. Functionally, T5-1 and T5-12 were found to be full agonists when measuring [Ca2+]i or ERK1/2 stimulation. The T5-12 phenotype was found to be due to agonist-induced stabilization of the receptor confining it to the cell membrane with subsequent failure to undergo internalization and receptor degradation. This occurred despite normal (referenced to T5-1) GRK-mediated receptor phosphorylation and β-arrestin recruitment by T5-12. Consistent with the lack of downregulation, T5-12 evoked much less functional desensitization of the [Ca2+]i (43% vs 78%) and ERK1/2 (64% vs > 95%) responses compared to T5-1, respectively. We conclude that TAS2R5 pathway signaling is malleable to a more favorable therapeutic profile by agonist-receptor interactions that preserve primary signaling and minimizes desensitization.","journal":"PLoS ONE","year":2025,"id":540348,"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":0.9582,"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":712739,"name":"Hannah R. Strzelinski","orcid":"0000-0002-8461-7061","position":1,"is_corresponding":false},{"id":390875,"name":"Stephen B. Liggett","orcid":"0000-0002-0128-3669","position":2,"is_corresponding":false},{"id":390872,"name":"Donghwa Kim","orcid":"0000-0002-8994-8513","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:52:38.861025Z","pmid":"39946435","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":[]}