Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial Cells
Human airway sweet (T1R2 + T1R3), umami (T1R1 + T1R3), and bitter taste receptors (T2Rs) are critical components of the innate immune system, acting as sensors to monitor pathogenic growth. T2Rs detect bacterial products or bitter compounds to drive nitric oxide (NO) production in both healthy and d...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/15/3/517 |
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| author | Derek B. McMahon Jennifer F. Jolivert Li Eon Kuek Nithin D. Adappa James N. Palmer Robert J. Lee |
| author_facet | Derek B. McMahon Jennifer F. Jolivert Li Eon Kuek Nithin D. Adappa James N. Palmer Robert J. Lee |
| author_sort | Derek B. McMahon |
| collection | DOAJ |
| description | Human airway sweet (T1R2 + T1R3), umami (T1R1 + T1R3), and bitter taste receptors (T2Rs) are critical components of the innate immune system, acting as sensors to monitor pathogenic growth. T2Rs detect bacterial products or bitter compounds to drive nitric oxide (NO) production in both healthy and diseased epithelial cell models. The NO enhances ciliary beating and also directly kills pathogens. Both sweet and umami receptors have been characterized to repress bitter taste receptor signaling in healthy and disease models. We hypothesized that the sweet/umami T1R3 antagonist lactisole may be used to alleviate bitter taste receptor repression in airway basal epithelial cells and enhance NO production. Here, we show that lactisole activates cAMP generation, though this occurs through a pathway independent of T1R3. This cAMP most likely signals through EPAC to increase ER Ca<sup>2+</sup> efflux. Stimulation with denatonium benzoate, a bitter taste receptor agonist which activates largely nuclear and mitochondrial Ca<sup>2+</sup> responses, resulted in a dramatically increased cytosolic Ca<sup>2+</sup> response in cells treated with lactisole. This cytosolic Ca<sup>2+</sup> signaling activated NO production in the presence of lactisole. Thus, lactisole may be useful coupled with bitter compounds as a therapeutic nasal rinse or spray to enhance beneficial antibacterial NO production in patients suffering from chronic inflammatory diseases such as chronic rhinosinusitis. |
| first_indexed | 2024-03-11T09:31:50Z |
| format | Article |
| id | doaj.art-de3cdae84fd84a42be61f2e8a4d87863 |
| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-11T09:31:50Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Nutrients |
| spelling | doaj.art-de3cdae84fd84a42be61f2e8a4d878632023-11-16T17:38:04ZengMDPI AGNutrients2072-66432023-01-0115351710.3390/nu15030517Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial CellsDerek B. McMahon0Jennifer F. Jolivert1Li Eon Kuek2Nithin D. Adappa3James N. Palmer4Robert J. Lee5Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USADepartment of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USAHuman airway sweet (T1R2 + T1R3), umami (T1R1 + T1R3), and bitter taste receptors (T2Rs) are critical components of the innate immune system, acting as sensors to monitor pathogenic growth. T2Rs detect bacterial products or bitter compounds to drive nitric oxide (NO) production in both healthy and diseased epithelial cell models. The NO enhances ciliary beating and also directly kills pathogens. Both sweet and umami receptors have been characterized to repress bitter taste receptor signaling in healthy and disease models. We hypothesized that the sweet/umami T1R3 antagonist lactisole may be used to alleviate bitter taste receptor repression in airway basal epithelial cells and enhance NO production. Here, we show that lactisole activates cAMP generation, though this occurs through a pathway independent of T1R3. This cAMP most likely signals through EPAC to increase ER Ca<sup>2+</sup> efflux. Stimulation with denatonium benzoate, a bitter taste receptor agonist which activates largely nuclear and mitochondrial Ca<sup>2+</sup> responses, resulted in a dramatically increased cytosolic Ca<sup>2+</sup> response in cells treated with lactisole. This cytosolic Ca<sup>2+</sup> signaling activated NO production in the presence of lactisole. Thus, lactisole may be useful coupled with bitter compounds as a therapeutic nasal rinse or spray to enhance beneficial antibacterial NO production in patients suffering from chronic inflammatory diseases such as chronic rhinosinusitis.https://www.mdpi.com/2072-6643/15/3/517T1R1T1R3umamilactisoleapoptosisnitric oxide |
| spellingShingle | Derek B. McMahon Jennifer F. Jolivert Li Eon Kuek Nithin D. Adappa James N. Palmer Robert J. Lee Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial Cells Nutrients T1R1 T1R3 umami lactisole apoptosis nitric oxide |
| title | Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial Cells |
| title_full | Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial Cells |
| title_fullStr | Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial Cells |
| title_full_unstemmed | Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial Cells |
| title_short | Utilizing the Off-Target Effects of T1R3 Antagonist Lactisole to Enhance Nitric Oxide Production in Basal Airway Epithelial Cells |
| title_sort | utilizing the off target effects of t1r3 antagonist lactisole to enhance nitric oxide production in basal airway epithelial cells |
| topic | T1R1 T1R3 umami lactisole apoptosis nitric oxide |
| url | https://www.mdpi.com/2072-6643/15/3/517 |
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