{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T02:58:24Z","timestamp":1790564304964,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T00:00:00Z","timestamp":1566259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL114471"],"award-info":[{"award-number":["HL114471"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL045967"],"award-info":[{"award-number":["HL045967"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:p>\n                    Bitter taste receptor\u201014 (TAS2R14) is a GPCR also expressed on human airway smooth muscle cells, which signals to intracellular [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ], resulting in relaxation of the airway, and is a novel target for bronchodilators. Here, we examine long\u2010term, agonist\u2010promoted down\u2010regulation of TAS2R14 expression because tachyphylaxis would be an undesirable therapeutic characteristic. Five TAS2R structurally distinct full agonists were studied to ascertain biasing away from down\u2010regulation. Agonist exposure for 18 h caused minimal desensitization by diphenhydramine (DPD) compared with ~50% desensitization with all other agonists. Agonists evoked \u03b2\u2010arrestin recruitment to TAS2R14, which was not seen with a phosphoacceptor\u2010deficient mutant, TAS2R14\u201010A. All agonists except for DPD also caused subsequent TAS2R14 internalization and trafficking\n                    <jats:italic>via<\/jats:italic>\n                    early and late endosomes to down\u2010regulation. TAS2R14\u201010A failed to undergo these events with any agonist. Molecular docking showed that DPD has specific interactions deep within a binding pocket that are not observed with the other agonists, which may lock the receptor in a conformation that does not internalize and therefore does not undergo down\u2010regulation. Thus, TAS2R14 is subject to \u03b2\u2010arrestin\u2010mediated internalization and subsequent down\u2010regulation with chronic exposure to most agonists. However, by manipulating the agonist structure, biasing toward G\u2010protein coupling but away from long\u2010term down\u2010regulation can be achieved.\u2014Woo, J. A., Casta\u00f1o, M., Goss, A., Kim, D., Lewandowski, E. M., Chen, Y., Liggett, S. B. Differential long\u2010term regulation of TAS2R14 by structurally distinct agonists. FASEB J. 33, 12213\u201012225 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201802627rr","type":"journal-article","created":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T17:10:50Z","timestamp":1566321050000},"page":"12213-12225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Differential long\u2010term regulation of TAS2R14 by structurally distinct agonists"],"prefix":"10.1096","volume":"33","author":[{"given":"Jung A.","family":"Woo","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Morsani College of Medicine Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Medicine University of South Florida Morsani College of Medicine Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Goss","sequence":"additional","affiliation":[{"name":"Department of Medicine University of South Florida Morsani College of Medicine Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghwa","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine University of South Florida Morsani College of Medicine Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Lewandowski","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of South Florida Morsani College of Medicine Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of South Florida Morsani College of Medicine Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen B.","family":"Liggett","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology University of South Florida Morsani College of Medicine Tampa Florida USA"},{"name":"Department of Medicine University of South Florida Morsani College of Medicine Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.27.070203.144206"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.01.024"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2015.05.005"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906034106"},{"key":"e_1_2_9_6_1","first-page":"L709","article-title":"Human lung cell \u03b2 2\u2010adrenergic receptors desensitize in response to in vivo administered \u03b2\u2010agonist","volume":"269","author":"Turki J.","year":"1995","journal-title":"Am. 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