JOURNAL OF THE CZECH PHARMACEUTICAL SOCIETY AND THE SLOVAK PHARMACEUTICAL SOCIETY

Čes. slov. farm. 2016, 65(4):132-138 | DOI: 10.36290/csf.2016.029

Cellular and molecular mechanisms of action of bitter compounds: recent knowledge and perspective

Milan Nagy*, Pavel Mučaji
Katedra farmakognózie a botaniky, Farmaceutická fakulta Univerzity Komenského v Bratislave, Bratislava, SR

This overview paper describes in its introductory part bitter-tasting herbal drugs in the context of their traditional use in the loss of appetite and digestive disorders. Then, it mentions current knowledge on signals origin in bitter taste receptors leading to different, unexpected physiological processes. Newly observed biological effects of bitter tastants are correlated with modern trends of their complex study with an aim to develop new drugs primarily acting on bitter taste receptors.

Keywords: T2R; bitter taste receptors; GPCR; bitters; glucose homeostasis; asthma; ghrelin; GLP-1; solitary chemosensory cells
Grants and funding:

Publikácia bola podporená grantom VEGA 1/0646/14.

Received: July 15, 2016; Accepted: August 15, 2016; Published: April 1, 2016  Show citation

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Nagy M, Mučaji P. Cellular and molecular mechanisms of action of bitter compounds: recent knowledge and perspective. Čes. slov. farm. 2016;65(4):132-138. doi: 10.36290/csf.2016.029.
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    References

    1. Scarborough J. Pharmacy in Pliny's Natural History. In: French R., Greenaway, F. eds. Science in the Early Roman Empire: Pliny the elder, his sources and influence, London and New York: Croom Helm and Oxford University Press 1986.
    2. Sneader W. Drug discovery: a history. Chichester: John Wiley & Sons Ltd. 2005. Go to original source...
    3. Janssen S., Laermans J., Verhulst P.-J., Thijs T., Tack J., Depoortere I. Bitter taste receptors and αα-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. PNAS 2011; 108, 2094-2099. Go to original source... Go to PubMed...
    4. McMullen M. K., Whitehouse J. M., Towell A. Bitters: Time for a New Paradigm. eCAM 2015, Article ID 670504, 8 pages, http://dx.doi.org/10.1155/2015/670504. Go to original source... Go to PubMed...
    5. Shah A. S., Ben-Shahar Y., Moninger T. O., Kline J. N., Welsh, M. J. Motile cilia of human airway epithelia are chemosensory. Science 2009; 325, 1131-1134. Go to original source... Go to PubMed...
    6. Wu S. V., Rozengurt N., Yang M., Young S. H., Sinnett-Smith J., Rozengurt, E. Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells. Proc. Natl. Acad. Sci. U.S.A. 2002; 99, 2392-2397. Go to original source... Go to PubMed...
    7. Clark A. A., Dotson C. D., Elson A. E., Voigt A., Boehm U., Meyerhof W., Steinle N. I., Munger S. D. TAS2R bitter taste receptors regulate thyroid function. FASEB J. 2014; 29, 164-172. Go to original source... Go to PubMed...
    8. Foster S. R., Porrello E. R., Purdue B., Chan H. W., Voigt A., Frenzel S., Hannan R. D., Moritz K. M., Simmons D. G., Molenaar P., Roura E., Boehm U., Meyerhof W., Thomas W. G. Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart. PLoS One 2013; 8, e64579. Go to original source... Go to PubMed...
    9. Kurihara K., Katsuragi Y., Matsuoka I., Kashiwayanagi M., Kumazawa T., Shoji T. Receptor mechanisms of bitter substances. Physiol. Behav. 1994; 56, 1125-1132. Go to original source... Go to PubMed...
    10. Nagy M., Mučaji P., Grančai D. Farmakognózia. Biologicky aktívne rastlinné metabolity a ich zdroje.1. vydanie Bratislava: Herba 2015.
    11. The IUCN Red List of Threatened Species 2016-1. http://cmsdocs.s3.amazonaws.com/summarystats/2016-1_Summary_Stats_Page_Documents/2016_1_RL_Stats_Table_1.pdf (14. 7. 2016).
    12. Cragg G. M., Newman D. J. Natural products: A continuing source of novel drug leads. Biochim. Biophys. Acta (BBA) - Gen. Subj. 2013; 1830, 3670-3695. Go to original source... Go to PubMed...
    13. Super Natural II, a database of natural products. http://bioinf-applied.charite.de/supernatural_new/index.php?site=home (14. 7. 2016).
    14. Wiener A., Shudler M., Levit A., Niv M. Y. BitterDB: a database of bitter compounds. Nucleic Acids Res. 2012; 40(Database issue), D413-419. Go to original source...
    15. Belitz H.-B., Wieser H. Bitter compounds: Occurrence and structure- activity relationships. Food Rev. Int. 1985; 1, 271-354. Go to original source...
    16. Chaudhari N., Roper, S. D. The cell biology of taste. J. Cell Biol. 2010; 190, 285-296. Go to original source... Go to PubMed...
    17. Caicedo A., Pereira E., Margolskee R. F., Roper S. D. Role of the G-protein subunit alpha-gustducin in taste cell responses to bitter stimuli. J. Neurosci. 2003; 23, 9947-9952. Go to original source... Go to PubMed...
    18. Zhang C.-H., Lifshitz L. M., Uy K. F., Ikebe M., Fogarty K. E., ZhuGe R. The Cellular and Molecular Basis of Bitter Tastant-Induced Bronchodilation. PLoS Biol. 2013; 11: e1001501. doi:10.1371/journal.pbio.1001501. Go to original source... Go to PubMed...
    19. Lee R. J., Xiong G., Kofonow J. M., Chen B., Lysenko A., Jiang P., Abraham V., Doghramji L., Adappa N. D., Palmer J. N., Kennedy D. W., Beauchamp G. K., Doulias P.-T., Ischiropoulos H., Kreindler J. L., Reed D. R., Cohen N. A. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J. Clin. Invest. 2012; 122, 4145-4159. Go to original source... Go to PubMed...
    20. Lee R. J., Kofonow J. M., Rosen P. L., Siebert A. P., Chen B., Doghramji, L., Xiong G., Adappa N. D., Palmer J. N., Kennedy D. W., Kreindler J. L., Margolskee R. F., Cohen, N. A. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Invest. 2014; 124, 1393-1405. Go to original source... Go to PubMed...
    21. Sharma P., Panebra A., Pera T., Tiegs B. C., Hershfeld A., Kenyon L. C., Deshpande D. A. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2016; 310: L365-L376. Go to original source... Go to PubMed...
    22. Dotson C. D., Zhang L., Xu H., Shin Y.-K., Vigues S., Ott S. H., Elson A. E. T., Choi H. J., Shaw H., Egan J. M., Mitchell B. D., Li X., Steinle N. I., Munger S. D. Bitter taste receptors influence glucose homeostasis. PLoS ONE 2008; 3: e3974. doi:10.1371/journal.pone.0003974. Go to original source... Go to PubMed...
    23. Park J., Kim K.-S., Kim K.-H., Lee I.-S., Jeong H., Kim Y., Jang H.-J. GLP-1 secretion is stimulated by 1,10-phenanthroline via colocalized T2R5 signal transduction in human enteroendocrine L cell. Biochem. Biophys. Res. Commun. 2015; 468, 306-311. Go to original source... Go to PubMed...
    24. Pham H., Hui H., Morvaridi S., Cai J., Zhang S., Tan J., Wu V., Levin N., Knudsen B., Goddard III W. A., Pandol S. J., Abrol R. A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells. Biochem. Biophys. Res. Commun. 2016; 475, 295-300. Go to original source... Go to PubMed...
    25. Choi E.-K., Kim K.-S., Yang H. J., Shin M.-H., Suh H.-W., Lee K.-B., Ahn K. S., Um J. Y., Lee S.-G., Lee B.-C., Jang H.-J. Hexane fraction of Citrus aurantium L. stimulates glucagon-like peptide-1 (GLP-1) secretion via membrane depolarization in NCI-H716 cells. Biochip J. 2012; 6, 41-47. Go to original source...
    26. Huang T., Lu K.-N., Pai Y.-P., Hsu C., Huang C. Role of GLP-1 in the Hypoglycemic Effects of Wild Bitter Gourd. eCAM 2013, Article ID 625892, 13 pages, http://dx.doi.org/10.1155/2013/625892. Go to original source... Go to PubMed...
    27. Kim K.-H., Kim K.-S., Shin M. H., Jang E. G., Kim E. Y., Lee J.-H., Ahn K. S., Um J.-Y., Jang H.-J. Aqueous extracts of Anemarrhena asphodeloides stimulate glucagon-like peptide-1 secretion in enteroendocrine NCI-H716 cells. Biochip J. 2013; 7, 188-193. Go to original source...
    28. Shin M.-H., Choi E.-K., Kim K.-S., Kim K.-H., Jang Y. P., Ahn K. S., Chung W.-S., Cha N. H., Jang H.-J. Hexane fractions of Bupleurum falcatum L. stimulates glucagon-like peptide-1 secretion through Gβγ??-mediated pathway. eCAM 2014, Article ID 982165, 8 pages, http://dx.doi.org/10.1155/2014/982165. Go to original source... Go to PubMed...
    29. Suh H.-W., Lee K.-B., Kim K.-S., Yang H. J., Choi E.-K., Shin M. H., Park Y. S., Na Y.-C., Ahn K.., Jang Y. P., Uma J. Y., Jang H.-J. A bitter herbal medicine Gentiana scabra root extract stimulates glucagon-like peptide-1 secretion and regulates blood glucose in db/db mouse. J. Ethnopharmacol. 2015; 172: 219-226. Go to original source... Go to PubMed...
    30. Kim K.-S., Cha N. H., Kim K.-W., Shin M. H., Kim K.-H., Lee I.-S., Chung W.-S., Song M.-Y., Jang H.-J. Transcriptomic analysis of the bitter taste receptor-mediated glucagon-like peptide-1 stimulation effect of quinine. BioChip J. 2013; 7: 386-392. Go to original source...
    31. Yu Y., Hao G., Zhang Q., Hua W., Wang M., Zhou W., Zong S., Huang M., Wen X. Berberine induces GLP-1 secretion through activation of bitter taste receptor pathways. Biochem. Pharmacol. 2015; 97: 173-177. Go to original source... Go to PubMed...
    32. Andreozzi P., Sarnelli G., Pesce M., Zito F. P., D'Alessandro A., Verlezza V., Palumbo I., Turco F., Esposito K., Cuomo R. The Bitter Taste Receptor Agonist Quinine Reduces Calorie Intake and Increases the Postprandial Release of Cholecystokinin in Healthy Subjects. J. Neurogastroenterol. Motil. 2015; 21, 511-519. Go to original source... Go to PubMed...
    33. Jeon T. I., Seo Y.-K., Osborne T. F. Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK. Biochem. J. 2011; 438, 33-37. Go to original source... Go to PubMed...
    34. Glatzel H. Der Einfluss von Bittermitteln auf Herzschlagvolumen, Herzschlagfrequenz und Blutdruck. Planta Med. 1968; 16, 82-94. Go to original source... Go to PubMed...
    35. Foster S. R., Blank K., Hoe L. S. E., Behrens M., Meyerhof W., Peart J. N., Thomas W. G. Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart. FASEB J. 2014; 28, 4497-4508. Go to original source... Go to PubMed...
    36. McMullen M. K., Whitehouse J. M., Whitton P. A., Towell A. Bitter tastants alter gastric-phase postprandial haemodynamics. J. Ethnopharmacol. 2014; 154, 719-727. Go to original source... Go to PubMed...
    37. Lund T. C., Kobs A. J., Kramer A., Nyquist M., Kuroki M. T., Osborn J., Lidke D. S., Low-Nam S. T., Blazar R., Tolar J. Bone Marrow Stromal and Vascular Smooth Muscle Cells Have Chemosensory Capacity via Bitter Taste Receptor Expression. PLoS ONE 2012; 8, e58945. doi:10.1371/journal.pone.0058945. Go to original source... Go to PubMed...
    38. Gam S., Guelfi K. J., Fournier P. A. New Insights into Enhancing Maximal Exercise Performance Through the Use of a Bitter Tastant. Sports Med. 2016, doi: 10.1007/s40279-016-0522-0,article in press. Go to original source... Go to PubMed...
    39. Mayer E. A. Gut feelings: the emerging biology of gut-brain communication. Nat. Rev. Neurosci. 2011; 12: 453-66. Go to original source... Go to PubMed...
    40. Singh N., Vrontakis M., Parkinson F., Chelikani P. Functional bitter taste receptors are expressed in brain cells. Biochem. Biophys. Res. Commun. 2011; 406: 146-151. Go to original source... Go to PubMed...
    41. Wolfle U., Elsholz F. A., Kersten A., Haarhaus B., Muller W. E., Schempp C. M. Expression and functional activity of the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes. Skin Pharmacol. Physiol. 2015; 28: 137-146. Go to original source... Go to PubMed...
    42. Mascie-Taylor C. G. N., McManus I. C., MacLarnon A. M., Lanigan P. M. The association between phenylthiocarbamide (PTC) tasting ability and psychometric variables. Behav. Genet. 1983; 13, 191-196. Go to original source... Go to PubMed...
    43. Macht M., Mueller J. Increased negative emotional responses in PROP supertasters. Physiol. Behav. 2007; 90, 466-472. Go to original source... Go to PubMed...
    44. Sagioglou C., Greitemeyer T. Bitter Taste Causes Hostility. Pers. Soc. Psychol. Bull. 2014; 40, 1589-1597. Go to original source... Go to PubMed...
    45. Sagioglou C., Greitemeyer T. Individual differences in bitter taste preferences are associated with antisocial personality traits. Appetite 2016; 96, 299e308. Go to original source... Go to PubMed...
    46. Deckmann K., Filipski K., Krasteva-Christ G., Fronius M., Althaus M., Rafiq A., Papadakis T., Renno L., Jurastow I., Wessels L., Wolff M., Schütz B., Weihe E., Chubanov V., Gudermann T., Klein J., Bschleipfer T., Kummer W. Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes. PNAS 2014; 111, 8287-8292. Go to original source... Go to PubMed...
    47. Zhai K., Yang Z., Zhu X., Nyirimigabo E., Mi Y., Wang Y., Liu Q., Man L., Wu S., Jin J., Ji G. Activation of bitter taste receptors (tas2rs) relaxes detrusor smooth muscle and suppresses overactive bladder symptoms. Oncotarget 2016; 7, 21156-21167. Go to original source... Go to PubMed...
    48. Clark A. A., Dotson C. D., Elson A. E. T., Voigt A., Boehm U., Meyerhof W., Steinle N. I., Munger S. D. TAS2R bitter taste receptors regulate thyroid function. FASEB J. 2015; 29, 164-172. Go to original source... Go to PubMed...
    49. Orsmark-Pietras C., James A., Konradsen J. R., Nordlund B., Soderhall C., Pulkkinen V., Pedroletti C., Daham K., Kupczyk M., Dahlen B., Kere J., Dahlen S. E., Hedlin G., Melen, E. Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics. Eur. Respir. J. 2013; 42, 65-78. Go to original source... Go to PubMed...
    50. Grassin-Delyle S., Naline E., Devillier, P. Taste receptors in asthma. Curr. Opin. Allergy Clin. Immunol. 2015; 15, 63-69. Go to original source... Go to PubMed...
    51. Ekoff M., Choi J. H., James A., Dahlen B., Nilsson G., Dahlen, S. E. Bitter taste receptor (TAS2R) agonists inhibit IgE-dependent mast cell activation. J. Allergy Clin. Immunol. 2014; 134, 475-47 Go to original source... Go to PubMed...

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