{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T02:35:15Z","timestamp":1773369315586,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2020-05670"],"award-info":[{"award-number":["RGPIN-2020-05670"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008794","name":"Research Manitoba","doi-asserted-by":"publisher","award":["7054"],"award-info":[{"award-number":["7054"]}],"id":[{"id":"10.13039\/100008794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Humans have at least 26 bitter taste receptors (T2Rs), and among these, bitter taste receptor 14 (T2R14) is highly expressed in both oral and extraoral tissues. Over 100 bitter ligands can activate T2R14, including hormones, vitamins, plant compounds, and peptides. Previous studies suggest that bitter tastants such as quinine and caffeine can inhibit G protein-coupled receptor kinases (GRKs) and delay T2R signal termination. Our earlier research showed that peptides from alcalase and chymotrypsin hydrolysates of beef proteins inhibited quinine-dependent calcium release through T2R4, with AGDDAPRAVF and ETSARHL showing the greatest effectiveness. However, the effect of these antagonistic peptides on other T2Rs, such as T2R14 signaling, remains unknown. This study aimed to evaluate the ability of these beef protein-derived peptides to activate or inhibit T2R14 signaling and the involvement of GRK2 in signal termination. Methods and Results: Our results indicate that the above two antagonist peptides significantly inhibit T2R14 activity. Furthermore, GRK2 knockout in HEK cells stably expressing T2R14 decreases intracellular calcium release, as measured by the area under the curve (AUC), and also delays the fall time (indication of desensitization) of the calcium response when exposed to the T2R14 agonist diphenhydramine (DPH) or beef protein-derived agonist peptide TMTL. Next, we measured the effects of these ligands on cAMP accumulation, and our results suggest no significant change in cAMP levels upon treatment with beef protein-derived peptides. Conclusions: Thus, this study showed that beef protein-derived peptides can function as both T2R inhibitors and mediate T2R14 desensitization through GRK2 signaling. These antagonistic food protein-derived peptides inform strategies to enhance nutrition, such as promoting healthier food choices by reducing bitterness and thereby improving the palatability of health-promoting bitter foods, such as fruit and vegetable extracts, as well as bitter medications.<\/jats:p>","DOI":"10.3390\/nu18060901","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T14:46:31Z","timestamp":1773326791000},"page":"901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beef-Derived Peptides Mediated Desensitization of Bitter Taste Receptor T2R14 Through GPCR Kinase 2"],"prefix":"10.3390","volume":"18","author":[{"given":"Nisha","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Oral Biology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, Canada"},{"name":"Manitoba Chemosensory Biology Research Group, University of Manitoba, Winnipeg, MB R3E 0W2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6188-2279","authenticated-orcid":false,"given":"Julia","family":"Drube","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Molekulare Zellbiologie, CMB\u2014Center for Molecular Biomedicine, Universit\u00e4tsklinikum Jena, Friedrich-Schiller-Universit\u00e4t Jena, Hans-Kn\u00f6ll-Stra\u00dfe 2, D-07745 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0884-9300","authenticated-orcid":false,"given":"Carsten","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Molekulare Zellbiologie, CMB\u2014Center for Molecular Biomedicine, Universit\u00e4tsklinikum Jena, Friedrich-Schiller-Universit\u00e4t Jena, Hans-Kn\u00f6ll-Stra\u00dfe 2, D-07745 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9025-2513","authenticated-orcid":false,"given":"Rotimi Emmanuel","family":"Aluko","sequence":"additional","affiliation":[{"name":"Manitoba Chemosensory Biology Research Group, University of Manitoba, Winnipeg, MB R3E 0W2, Canada"},{"name":"Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"},{"name":"Richardson Center for Food Technology and Research, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1129-7957","authenticated-orcid":false,"given":"Prashen","family":"Chelikani","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, Canada"},{"name":"Manitoba Chemosensory Biology Research Group, University of Manitoba, Winnipeg, MB R3E 0W2, Canada"},{"name":"Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, Canada"},{"name":"Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.foodchem.2016.03.058","article-title":"Sequence, taste and umami-enhancing effect of the peptides separated from soy sauce","volume":"206","author":"Zhuang","year":"2016","journal-title":"Food Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.foodres.2016.08.010","article-title":"Food protein-originating peptides as tastants\u2014Physiological, technological, sensory, and bioinformatic approaches","volume":"89","author":"Iwaniak","year":"2016","journal-title":"Food Res. 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