{"doi":"10.1165/rcmb.2024-0231oc","title":"TMEM16A Antagonism: Therapeutic Potential with Desensitization of β-Agonist Responsiveness in Asthma","abstract":"Abstract The efficacy of β-agonists in asthma is severely limited by β-adrenoceptor desensitization, which results in poorly managed symptoms and refractory bronchoconstriction. Thus, there is a need to identify novel therapeutic pathways and to clarify the relationship between novel therapeutics and functional β-adrenoceptor responsiveness. We have previously demonstrated that acute antagonism of the calcium-activated chloride channel, transmembrane member 16A (TMEM16A), relaxes airway smooth muscle (ASM). We sought to determine the efficacy and role of TMEM16A antagonism in the context of desensitization β-adrenoceptor responsiveness. For these studies, we exposed murine tracheal rings on wire myography and precision-cut lung slices to contractile mediators in the presence or absence of TMEM16A antagonists and β-agonists with or without prior β-adrenoceptor desensitization. Contractile studies were also performed with human tracheal and bronchial ASM. Finally, the ability of TMEM16A antagonism to prevent desensitization of β2-adrenoceptor–induced cAMP synthesis was measured in human ASM cells. From these studies, we demonstrate that acute TMEM16A antagonism is effective in relaxing β-agonist–desensitized ASM in central and peripheral murine ASM and human ASM. Furthermore, we demonstrate that chronic pretreatment with TMEM16A antagonists prevents functional desensitization of β-agonist responsiveness in mouse and human upper airways and prevents desensitization of β-agonist–mediated cAMP production in human ASM cells. Taken together, the present study demonstrates a favorable therapeutic profile of TMEM16A antagonism for ASM relaxation despite functional desensitization of β-agonist responsiveness, which may be a novel therapeutic approach in the face of β-adrenoceptor tachyphylaxis.","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2024,"id":466759,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"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":1299304,"name":"Aisha Kuforiji","orcid":null,"position":1,"is_corresponding":false},{"id":617602,"name":"Yi Zhang","orcid":"0000-0003-0351-5184","position":2,"is_corresponding":false},{"id":1299305,"name":"Dingbang Xu","orcid":null,"position":3,"is_corresponding":false},{"id":458722,"name":"Jose F. Perez‐Zoghbi","orcid":"0000-0002-7554-6468","position":4,"is_corresponding":false},{"id":485294,"name":"Charles W. Emala","orcid":"0000-0003-0248-4662","position":5,"is_corresponding":false},{"id":782184,"name":"Jennifer Danielsson","orcid":null,"position":6,"is_corresponding":false},{"id":415784,"name":"Amy D. Wu","orcid":"0000-0003-4983-2724","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:05:06.743102Z","pmid":"39560606","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":[]}