β2-Adrenergic Receptors Chaperone Trapped Bitter Taste Receptor 14 to the Cell Surface as a Heterodimer and Exert Unidirectional Desensitization of Taste Receptor Function

Kim, Donghwa; Pauer, Susan H.; Yong, Hwan Mee; An, Steven S.; Liggett, Stephen B.

doi:10.1074/jbc.m116.722736

Cited by 29 publications

(34 citation statements)

References 26 publications

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“…Second, we demonstrate that flavones activate T2R14 in primary sinonasal epithelial cell cilia. T2R14 is also expressed in bronchial cilia (101) and airway smooth muscle cells (116). This is the first demonstration of T2R14 in sinonasal cilia, and the finding that T2R14 closely co-localizes (Ͻ7 nm) with T2R38 is important and novel.…”

Section: Discussionmentioning

confidence: 65%

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Hariri¹,

McMahon²,

Chen³

et al. 2017

Journal of Biological Chemistry

106

176

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Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ∼20% of adult antibiotic prescriptions in the United States. Because of the rise of resistant microorganisms, there is a critical need to better understand how to stimulate and/or enhance innate immune responses as a therapeutic modality to treat respiratory infections. We recently identified bitter taste receptors (taste family type 2 receptors, or T2Rs) as important regulators of sinonasal immune responses and potentially important therapeutic targets. Here, we examined the immunomodulatory potential of flavones, a class of flavonoids previously demonstrated to have antibacterial and anti-inflammatory effects. Some flavones are also T2R agonists. We found that several flavones inhibit Muc5AC and inducible NOS up-regulation as well as cytokine release in primary and cultured airway cells in response to several inflammatory stimuli. This occurs at least partly through inhibition of protein kinase C and receptor tyrosine kinase activity. We also demonstrate that sinonasal ciliated epithelial cells express T2R14, which closely co-localizes (<7 nm) with the T2R38 isoform. Heterologously expressed T2R14 responds to multiple flavones. These flavones also activate T2R14-driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance. polymorphisms encode functional (PAV:roline, lanine, andaline at positions 49, 262, and 296, respectively) or non-functional (AVI: lanine,aline, soleucine at positions 49, 262, and 296, respectively) T2R38. Our data demonstrate that T2R14 in sinonasal cilia is a potential therapeutic target for upper respiratory infections and that flavones may have clinical potential as topical therapeutics, particularly in T2R38 AVI/AVI individuals.

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Section: Discussionmentioning

confidence: 65%

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Hariri¹,

McMahon²,

Chen³

et al. 2017

Journal of Biological Chemistry

106

176

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“…This represents somewhat of a paradox, especially since some of the denatonium responsive T2Rs (T2R4 and T2R16) have recently been demonstrated to be expressed in ciliated cells . A possible explanation for this apparent contradiction may rest in the fact that the HEK‐293 cells—though useful in studying the basic science of T2R receptors—cannot be expected to fully recapitulate a receptor in vivo, where hetero‐oligomerization (both with other T2Rs and other families of G‐protein‐coupled receptors [GPCRs], as demonstrated by the recent work by Kim et al …”

Section: Discussionmentioning

confidence: 99%

Denatonium‐induced sinonasal bacterial killing may play a role in chronic rhinosinusitis outcomes

Carey

Workman

Hatten

et al. 2017

Int Forum Allergy Rhinol

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Background Sinonasal bitter taste receptors (T2Rs) contribute to upper airway innate immunity and correlate with chronic rhinosinusitis (CRS) clinical outcomes. A subset of T2Rs expressed on sinonasal solitary chemosensory cells (SCCs) are activated by denatonium, resulting in a calcium-mediated secretion of bactericidal antimicrobial peptides (AMPs) in neighboring ciliated epithelial cells. We hypothesized that there is patient variability in the amount of bacterial killing induced by different concentrations of denatonium and that the differences correlate with CRS clinical outcomes. Methods Bacterial growth inhibition was quantified after mixing bacteria with airway surface liquid (ASL) collected from denatonium-stimulated sinonasal air-liquid interface (ALI) cultures. Patient ASL bacterial killing at 0.1 mM denatonium and baseline characteristics and sinus surgery outcomes were compared between these populations. Results There is variability in the degree of denatonium-induced bacterial killing between patients. In CRS with nasal polyps (CRSwNP), patients with increased bacterial killing after stimulation with low levels of denatonium undergo significantly more functional endoscopic sinus surgeries (FESSs) (p = 0.037) and have worse 6-month post-FESS 22-item Sino-Nasal Outcome Test (SNOT-22) scores (p = 0.012). Conclusion Bacterial killing after stimulation with low levels of denatonium correlates with number of prior FESS and postoperative SNOT-22 scores in CRSwNP. Some symptoms of CRS in patients with hyperresponsiveness to low levels of denatonium may be due to increased airway immune activity or inherent disease severity.

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“…[Ca 2+ ] i assays were performed by loading the cells in 96‐well plates with Fluo‐4 (Thermo Fisher Scientific, Waltham, MA, USA) and utilizing a Flex Station 3 (Molecular Devices, Sunnyvale, CA, USA). Transfections were carried out using the previously described (20) FLAG‐tagged TAS2R14 (or the mutant) in pcDNA3 using Lipofectamine 2000 as previously described (19). Mutagenesis of TAS2R14 cDNA was performed in order to change the encoded serines or threonines to alanine at amino acid positions 215, 219, 223, 224, and 232 (in the third intracellular loop) and 291, 293, 308, 316, and 317 (in the cytoplasmic tail).…”

Section: Methodsmentioning

confidence: 99%

Differential long‐term regulation of TAS2R14 by structurally distinct agonists

et al. 2019

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Bitter taste receptor‐14 (TAS2R14) is a GPCR also expressed on human airway smooth muscle cells, which signals to intracellular [Ca2+], resulting in relaxation of the airway, and is a novel target for bronchodilators. Here, we examine long‐term, agonist‐promoted down‐regulation 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‐regulation. Agonist exposure for 18 h caused minimal desensitization by diphenhydramine (DPD) compared with ~50% desensitization with all other agonists. Agonists evoked β‐arrestin recruitment to TAS2R14, which was not seen with a phosphoacceptor‐deficient mutant, TAS2R14‐10A. All agonists except for DPD also caused subsequent TAS2R14 internalization and trafficking via early and late endosomes to down‐regulation. TAS2R14‐10A 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‐regulation. Thus, TAS2R14 is subject to β‐arrestin‐mediated internalization and subsequent down‐regulation with chronic exposure to most agonists. However, by manipulating the agonist structure, biasing toward G‐protein coupling but away from long‐term down‐regulation can be achieved.—Woo, J. A., Castaño, M., Goss, A., Kim, D., Lewandowski, E. M., Chen, Y., Liggett, S. B. Differential long‐term regulation of TAS2R14 by structurally distinct agonists. FASEB J. 33, 12213‐12225 (2019). http://www.fasebj.org

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β2-Adrenergic Receptors Chaperone Trapped Bitter Taste Receptor 14 to the Cell Surface as a Heterodimer and Exert Unidirectional Desensitization of Taste Receptor Function

Cited by 29 publications

References 26 publications

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Denatonium‐induced sinonasal bacterial killing may play a role in chronic rhinosinusitis outcomes

Differential long‐term regulation of TAS2R14 by structurally distinct agonists

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