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Thus, there is a need to identify novel therapeutic pathways and to clarify the relationship between novel therapeutics and functional \u03b2-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 \u03b2-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 \u03b2-agonists with or without prior \u03b2-adrenoceptor desensitization. Contractile studies were also performed with human tracheal and bronchial ASM. Finally, the ability of TMEM16A antagonism to prevent desensitization of \u03b22-adrenoceptor\u2013induced cAMP synthesis was measured in human ASM cells. From these studies, we demonstrate that acute TMEM16A antagonism is effective in relaxing \u03b2-agonist\u2013desensitized ASM in central and peripheral murine ASM and human ASM. Furthermore, we demonstrate that chronic pretreatment with TMEM16A antagonists prevents functional desensitization of \u03b2-agonist responsiveness in mouse and human upper airways and prevents desensitization of \u03b2-agonist\u2013mediated 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 \u03b2-agonist responsiveness, which may be a novel therapeutic approach in the face of \u03b2-adrenoceptor tachyphylaxis.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0231oc","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T10:44:50Z","timestamp":1732013090000},"page":"510-519","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":5,"title":["TMEM16A Antagonism: Therapeutic Potential with Desensitization of \u03b2-Agonist Responsiveness in Asthma"],"prefix":"10.1093","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4983-2724","authenticated-orcid":false,"given":"Amy","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New 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