Advertisement

Regulation of Intracellular Calcium by Bitter Taste Receptors on Airway Smooth Muscle

  • Deepak A. DeshpandeEmail author
  • Stephen B. Liggett
Chapter

Abstract

Recent studies have demonstrated the expression of bitter taste receptors (BTRs) on airway smooth muscle (ASM) using human, mouse, and guinea-pig airways. BTRs, belonging to the Tas2R family, are activated by a wide range of synthetic and natural compounds. However, these receptors are evolved with low, but broad-spectrum affinity for their ligands. Stimulation of BTRs with known bitter tastants results in an elevation of basal intracellular calcium concentration in cultured human ASM cells, similar to stimulation with other Gq-coupled G protein coupled receptors. Studies in human and murine ASM cells have demonstrated that bitter tastant-induced calcium elevation is Gβγ-, phospholipase C-, inositol trisphosphate (IP3)-, and IP3-receptor dependent. Very interestingly, bitter tastants induce efficacious ASM relaxation and bronchodilation in airways obtained from human, mouse, and guinea-pig lungs. At least two potential mechanisms for bitter-tastant-induced ASM relaxation have been proposed: (1) activation of calcium-activated potassium channels by calcium induced by bitter tastants, resulting in membrane hyperpolarization and ASM relaxation, and (2) inhibition of calcium entry via voltage-dependent calcium channels upon stimulation of ASM with contractile agonists, thereby inhibiting contraction. Nevertheless, the paradoxical effect of bitter tastants on ASM tone is intriguing and establishes Tas2 receptors as a novel class of therapeutic targets in the treatment of obstructive airway diseases such as asthma and chronic obstructive pulmonary disease.

Keywords

Taste receptors Bitter Tas2 Gustducin Chloroquine 

References

  1. 1.
    Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ and Zuker CS. A novel family of mammalian taste receptors. Cell 100: 693–702, 2000.PubMedCrossRefGoogle Scholar
  2. 2.
    An SS, Robinett KS, Deshpande DA, Wang WC and Liggett SB. Reply to: Activation of BK channels may not be required for bitter tastant-induced bronchodilation. Nat Med 18: 650–651, 2012.PubMedCrossRefGoogle Scholar
  3. 3.
    An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, Panettieri RA, Jr. and Liggett SB. TAS2R activation promotes airway smooth muscle relaxation despite beta(2)-adrenergic receptor tachyphylaxis. Am J Physiol Lung Cell Mol Physiol 303: L304-L311, 2012.PubMedCrossRefGoogle Scholar
  4. 4.
    Behrens M and Meyerhof W. Oral and extraoral bitter taste receptors. Results Probl Cell Differ 52: 87–99, 2010.PubMedCrossRefGoogle Scholar
  5. 5.
    Behrens M, Reichling C, Batram C, Brockhoff A and Meyerhof W. Bitter taste receptors and their cells. Ann N Y Acad Sci 1170: 111–115, 2009.PubMedCrossRefGoogle Scholar
  6. 6.
    Belvisi MG, Dale N, Birrell MA and Canning BJ. Bronchodilator activity of bitter tastants in human tissue. Nat Med 17: 776–778, 2011.PubMedCrossRefGoogle Scholar
  7. 7.
    Brockhoff A, Behrens M, Niv MY and Meyerhof W. Structural requirements of bitter taste receptor activation. Proc Natl Acad Sci U S A 107: 11110–11115, 2010.PubMedCrossRefGoogle Scholar
  8. 8.
    Caicedo A, Pereira E, Margolskee RF and Roper SD. Role of the G-protein subunit alpha-gustducin in taste cell responses to bitter stimuli. J Neurosci 23: 9947–9952, 2003.PubMedGoogle Scholar
  9. 9.
    Clapp TR, Trubey KR, Vandenbeuch A, Stone LM, Margolskee RF, Chaudhari N and Kinnamon SC. Tonic activity of Galpha-gustducin regulates taste cell responsivity. FEBS Lett 582: 3783–3787, 2008.PubMedCrossRefGoogle Scholar
  10. 10.
    Damak S, Rong M, Yasumatsu K, Kokrashvili Z, Perez CA, Shigemura N, Yoshida R, Mosinger B, Jr., Glendinning JI, Ninomiya Y and Margolskee RF. Trpm5 null mice respond to bitter, sweet, and umami compounds. Chem Senses 31: 253–264, 2006.PubMedCrossRefGoogle Scholar
  11. 11.
    Deshpande DA and Penn RB. Targeting G protein-coupled receptor signaling in asthma. Cell Signal 18: 2105–2120, 2006.PubMedCrossRefGoogle Scholar
  12. 12.
    Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS and Liggett SB. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat Med 16: 1299–1304, 2010.PubMedCrossRefGoogle Scholar
  13. 13.
    Gosling M, Poll C and Li S. TRP channels in airway smooth muscle as therapeutic targets. Naunyn Schmiedebergs Arch Pharmacol 371: 277–284, 2005.PubMedCrossRefGoogle Scholar
  14. 14.
    He W, Yasumatsu K, Varadarajan V, Yamada A, Lem J, Ninomiya Y, Margolskee RF and Damak S. Umami taste responses are mediated by alpha-transducin and alpha-gustducin. J Neurosci 24: 7674–7680, 2004.PubMedCrossRefGoogle Scholar
  15. 15.
    Huang L, Shanker YG, Dubauskaite J, Zheng JZ, Yan W, Rosenzweig S, Spielman AI, Max M and Margolskee RF. Ggamma13 colocalizes with gustducin in taste receptor cells and mediates IP3 responses to bitter denatonium. Nat Neurosci 2: 1055–1062, 1999.PubMedCrossRefGoogle Scholar
  16. 16.
    Kinnamon SC. Taste receptor signalling - from tongues to lungs. Acta Physiol (Oxf) 204: 158–168, 2012.CrossRefGoogle Scholar
  17. 17.
    Kinnamon SC and Margolskee RF. Mechanisms of taste transduction. Curr Opin Neurobiol 6: 506–513, 1996.PubMedCrossRefGoogle Scholar
  18. 18.
    Krasteva G, Canning BJ, Hartmann P, Veres TZ, Papadakis T, Muhlfeld C, Schliecker K, Tallini YN, Braun A, Hackstein H, Baal N, Weihe E, Schutz B, Kotlikoff M, Ibanez-Tallon I and Kummer W. Cholinergic chemosensory cells in the trachea regulate breathing. Proc Natl Acad Sci U S A 2011.Google Scholar
  19. 19.
    McLaughlin SK, McKinnon PJ and Margolskee RF. Gustducin is a taste-cell-specific G protein closely related to the transducins. Nature 357: 563–569, 1992.PubMedCrossRefGoogle Scholar
  20. 20.
    McLaughlin SK, McKinnon PJ, Robichon A, Spickofsky N and Margolskee RF. Gustducin and transducin: a tale of two G proteins. Ciba Found Symp 179: 186–196, 1993.PubMedGoogle Scholar
  21. 21.
    Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G and Behrens M. The molecular receptive ranges of human TAS2R bitter taste receptors. Chem Senses 35: 157–170, 2010.PubMedCrossRefGoogle Scholar
  22. 22.
    Mizuta K, Mizuta F, Xu D, Masaki E, Panettieri RA, Jr. and Emala CW. Gi-coupled gamma-aminobutyric acid-B receptors cross-regulate phospholipase C and calcium in airway smooth muscle. Am J Respir Cell Mol Biol 45: 1232–1238, 2011.PubMedCrossRefGoogle Scholar
  23. 23.
    Mizuta K, Xu D, Pan Y, Comas G, Sonett JR, Zhang Y, Panettieri RA, Jr., Yang J and Emala CW, Sr. GABAA receptors are expressed and facilitate relaxation in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 294: L1206-L1216, 2008.PubMedCrossRefGoogle Scholar
  24. 24.
    Osawa Y, Xu D, Sternberg D, Sonett JR, D'Armiento J, Panettieri RA and Emala CW. Functional expression of the GABAB receptor in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 291: L923-L931, 2006.PubMedCrossRefGoogle Scholar
  25. 25.
    Palmer K.R. The Pharmacology and Signaling of bitter, sweet, and Umami taste signaling. Molecular Interventions 7: 87–98, 2007.PubMedCrossRefGoogle Scholar
  26. 26.
    Perez CA, Huang L, Rong M, Kozak JA, Preuss AK, Zhang H, Max M and Margolskee RF. A transient receptor potential channel expressed in taste receptor cells. Nat Neurosci 5: 1169–1176, 2002.PubMedCrossRefGoogle Scholar
  27. 27.
    Perez CA, Margolskee RF, Kinnamon SC and Ogura T. Making sense with TRP channels: store-operated calcium entry and the ion channel Trpm5 in taste receptor cells. Cell Calcium 33: 541–549, 2003.PubMedCrossRefGoogle Scholar
  28. 28.
    Pietras CO, James A, Konradsen JR, Nordlund B, Soderhall C, Pulkkinen V, Pedroletti C, Daham K, Kupczyk M, Dahlen B, Kere J, Dahlen SE, Hedlin G and Melen E. Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics. Eur Respir J 2012.Google Scholar
  29. 29.
    Pulkkinen V, Manson ML, Safholm J, Adner M and Dahlen SE. The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea. Am J Physiol Lung Cell Mol Physiol 303: L956-L966, 2012.PubMedCrossRefGoogle Scholar
  30. 30.
    Pydi SP, Upadhyaya J, Singh N, Pal BR and Chelikani P. Recent advances in structure and function studies on human bitter taste receptors. Curr Protein Pept Sci 13: 501–508, 2012.PubMedCrossRefGoogle Scholar
  31. 31.
    Rossler P, Boekhoff I, Tareilus E, Beck S, Breer H and Freitag J. G protein beta-gamma complexes in circumvallate taste cells involved in bitter transduction. Chem Senses 25: 413–421, 2000.PubMedCrossRefGoogle Scholar
  32. 32.
    Rossler P, Kroner C, Freitag J, Noe J and Breer H. Identification of a phospholipase C beta subtype in rat taste cells. Eur J Cell Biol 77: 253–261, 1998.PubMedCrossRefGoogle Scholar
  33. 33.
    Saxena H, Deshpande DA, Tiegs BC, Yan H, Battafarano RJ, Burrows WM, Damera G, Panettieri RA, DuBose TD, Jr., An SS and Penn RB. The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH. Br J Pharmacol 166: 981–990, 2012.PubMedCrossRefGoogle Scholar
  34. 34.
    Shah AS, Ben-Shahar Y, Moninger TO, Kline JN and Welsh MJ. Motile cilia of human airway epithelia are chemosensory. Science 325: 1131–1134, 2009.PubMedCrossRefGoogle Scholar
  35. 35.
    Singh N, Pydi SP, Upadhyaya J and Chelikani P. Structural basis of activation of bitter taste receptor T2R1 and comparison with Class A G-protein-coupled receptors (GPCRs). J Biol Chem 286: 36032–36041, 2011.PubMedCrossRefGoogle Scholar
  36. 36.
    Tizzano M, Cristofoletti M, Sbarbati A and Finger TE. Expression of taste receptors in solitary chemosensory cells of rodent airways. BMC Pulm Med 11: 3, 2011.PubMedCrossRefGoogle Scholar
  37. 37.
    Tizzano M, Dvoryanchikov G, Barrows JK, Kim S, Chaudhari N and Finger TE. Expression of Galpha14 in sweet-transducing taste cells of the posterior tongue. BMC Neurosci 9: 110, 2008.PubMedCrossRefGoogle Scholar
  38. 38.
    Tizzano M and Finger TE. Chemosensors in the nose: guardians of the airways. Physiology (Bethesda) 28: 51–60, 2013.CrossRefGoogle Scholar
  39. 39.
    Tizzano M, Gulbransen BD, Vandenbeuch A, Clapp TR, Herman JP, Sibhatu HM, Churchill ME, Silver WL, Kinnamon SC and Finger TE. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci U S A 107: 3210–3215, 2010.PubMedCrossRefGoogle Scholar
  40. 40.
    Vandenbeuch A and Kinnamon SC. Why do taste cells generate action potentials? J Biol 8: 42, 2009.PubMedCrossRefGoogle Scholar
  41. 41.
    Yan W, Sunavala G, Rosenzweig S, Dasso M, Brand JG and Spielman AI. Bitter taste transduced by PLC-beta(2)-dependent rise in IP(3) and alpha-gustducin-dependent fall in cyclic nucleotides. Am J Physiol Cell Physiol 280: C742-C751, 2001.PubMedGoogle Scholar
  42. 42.
    Zancanaro C, Caretta CM, Merigo F, Cavaggioni A and Osculati F. alpha-Gustducin expression in the vomeronasal organ of the mouse. Eur J Neurosci 11: 4473–4475, 1999.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang CH, Chen C, Lifshitz LM, Fogarty KE, Zhu MS and ZhuGe R. Activation of BK channels may not be required for bitter tastant-induced bronchodilation. Nat Med 18: 648–650, 2012.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang CH, Lifshitz LM, Uy KF, Ikebe M, Fogarty KE and ZhuGe R. The cellular and molecular basis of bitter tastant-induced bronchodilation. PLoS Biol 11: e1001501, 2013.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang Z, Zhao Z, Margolskee R and Liman E. The transduction channel TRPM5 is gated by intracellular calcium in taste cells. J Neurosci 27: 5777–5786, 2007.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of Medicine, Pulmonary and Critical Care Medicine, School of MedicineUniversity of MarylandBaltimoreUSA
  2. 2.Morsani College of MedicineUniversity of South FloridaTampaUSA

Personalised recommendations