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Bitter taste receptor agonists regulate epithelial two-pore potassium channels via cAMP signaling

  • Kohanski, Michael A.1
  • Brown, Lauren2
  • Orr, Melissa2
  • Tan, Li Hui1
  • Adappa, Nithin D.1
  • Palmer, James N.1
  • Rubenstein, Ronald C.2, 3, 4
  • Cohen, Noam A.1, 5, 6
  • 1 University of Pennsylvania Medical Center, Perelman School of Medicine, 5th Floor Ravdin Building, 3400 Spruce Street, Philadelphia, PA, USA , Philadelphia (United States)
  • 2 The Children’s Hospital of Philadelphia, Philadelphia, PA, USA , Philadelphia (United States)
  • 3 University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA , Philadelphia (United States)
  • 4 Washington University in St. Louis School of Medicine, St. Louis, MO, USA , St. Louis (United States)
  • 5 Corporal Michael J. Crescenz Veterans Administration Medical Center, Philadelphia, PA, USA , Philadelphia (United States)
  • 6 Monell Chemical Senses Institute, Philadelphia, PA, USA , Philadelphia (United States)
Published Article
Respiratory Research
BioMed Central
Publication Date
Jan 28, 2021
DOI: 10.1186/s12931-021-01631-0
Springer Nature


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.

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