Abstract
BackgroundEpithelial solitary chemosensory cell (tuft cell) bitter taste signal transduction occurs through G protein coupled receptors and calcium-dependent signaling pathways. Type II taste cells, which utilize the same bitter taste signal transduction pathways, may also utilize cyclic adenosine monophosphate (cAMP) as an independent signaling messenger in addition to calcium.MethodsIn this work we utilized specific pharmacologic inhibitors to interrogate the short circuit current (Isc) of polarized nasal epithelial cells mounted in Ussing chambers to assess the electrophysiologic changes associated with bitter agonist (denatonium) treatment. We also assessed release of human β-defensin-2 from polarized nasal epithelial cultures following treatment with denatonium benzoate and/or potassium channel inhibitors.ResultsWe demonstrate that the bitter taste receptor agonist, denatonium, decreases human respiratory epithelial two-pore potassium (K2P) current in polarized nasal epithelial cells mounted in Ussing chambers. Our data further suggest that this occurs via a cAMP-dependent signaling pathway. We also demonstrate that this decrease in potassium current lowers the threshold for denatonium to stimulate human β-defensin-2 release.ConclusionsThese data thus demonstrate that, in addition to taste transducing calcium-dependent signaling, bitter taste receptor agonists can also activate cAMP-dependent respiratory epithelial signaling pathways to modulate K2P currents. Bitter-agonist regulation of potassium currents may therefore serve as a means of rapid regional epithelial signaling, and further study of these pathways may provide new insights into regulation of mucosal ionic composition and innate mechanisms of epithelial defense.
Highlights
Epithelial solitary chemosensory cell bitter taste signal transduction occurs through G protein coupled receptors and calcium-dependent signaling pathways
Gustatory taste signaling in type II taste cells, which are most similar in terms of taste transduction pathways to SCCs, occurs through Gβγ-mediated signaling involving phospholipase Cβ2 (PLCβ2), generation of inositol triphosphate (IP3) and subsequent TRPM5-dependent calcium-mediated paracrine signaling involving release of adenosine triphosphate (ATP) and acetylcholine [14,15,16,17], while Gα-gustducin activates phosphodiesterases to decrease cyclic adenosine monophosphate [14]
To explore the electrophysiologic changes in sinonasal epithelia associated with denatonium benzoate treatment, we utilized Ussing chambers to interrogate the short circuit current (Isc) and transepithelial resistance of human sinonasal cells grown under air–liquid interface (ALI) conditions
Summary
Epithelial solitary chemosensory cell (tuft cell) bitter taste signal transduction occurs through G protein coupled receptors and calcium-dependent signaling pathways. Gustatory taste signaling in type II taste cells, which are most similar in terms of taste transduction pathways to SCCs, occurs through Gβγ-mediated signaling involving PLCβ2, generation of inositol triphosphate (IP3) and subsequent TRPM5-dependent calcium-mediated paracrine signaling involving release of adenosine triphosphate (ATP) and acetylcholine [14,15,16,17], while Gα-gustducin activates phosphodiesterases to decrease cyclic adenosine monophosphate (cAMP) [14]. Stimulation of human sinonasal SCCs with the bitter tasting molecule denatonium, which broadly targets gustducin-coupled T2Rs expressed on SCCs [8, 20] and does not stimulate downstream effects of nasal ciliary T2Rs [21], results in a localized calcium flux in the epithelium and release of β-defensins through a PLCβ-2 and TRPM5 dependent process to contribute to the innate immune response [4]. Bitter taste receptor agonists can decrease epithelial cAMP levels [22, 23], whether or not G α-gustducin activates phosphodiesterases in SCCs as the mechanism of this effect is largely unknown
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