Extraoral bitter taste receptors in health and disease

Journal of General Physiology

Volumn 149, Issue 2, 2017, Pages 181-197

  Lu, Ping ^a   Zhang, Cheng Hai ^a   Lifshitz, Lawrence M ^a   ZhuGe, Ronghua ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

G PROTEIN COUPLED RECEPTOR; TASTE RECEPTORS, TYPE 2;

ANIMAL; GENETICS; HUMAN; INNATE IMMUNITY; METABOLISM; MUSCLE CELL; MUSCLE CONTRACTION; PARACRINE SIGNALING; PHYSIOLOGY; RESPIRATORY MUCOSA;

ANIMALS; HUMANS; IMMUNITY, INNATE; MUSCLE CELLS; MUSCLE CONTRACTION; PARACRINE COMMUNICATION; RECEPTORS, G-PROTEIN-COUPLED; RESPIRATORY MUCOSA;

EID: 85012918828     PISSN: 00221295     EISSN: 15407748     Source Type: Journal    
DOI: 10.1085/jgp.201611637     Document Type: Review

References (148)

1. Adappa, N.D., Z. Zhang, J.N. Palmer, D.W. Kennedy, L. Doghramji, A. Lysenko, D.R. Reed, T. Scott, N.W. Zhao, D. Owens, et al. 2014. The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery. Int. Forum Allergy Rhinol. 4:3-7. http://dx.doi.org /10.1002 /alr .21253
2. Adappa, N.D., D. Farquhar, J.N. Palmer, D.W. Kennedy, L. Doghramji, S.A. Morris, D. Owens, C. Mansfield, A. Lysenko, R.J. Lee, et al. 2016a. TAS2R38 genotype predicts surgical outcome in nonpolypoid chronic rhinosinusitis. Int. Forum Allergy Rhinol. 6:25-33. http://dx.doi.org /10.1002 /alr .21666
3. Adappa, N.D., C.M. Truesdale, A.D. Workman, L. Doghramji, C. Mansfield, D.W. Kennedy, J.N. Palmer, B.J. Cowart, and N.A. Cohen. 2016c. Correlation of T2R38 taste phenotype and in vitro biofilm formation from nonpolypoid chronic rhinosinusitis patients. Int. Forum Allergy Rhinol. 6:783-791. http://dx.doi.org /10.1002 /alr .21803
4. Adappa, N.D., A.D. Workman, D. Hadjiliadis, D.J. Dorgan, D. Frame, S. Brooks, L. Doghramji, J.N. Palmer, C. Mansfield, D.R. Reed, and N.A. Cohen. 2016b. T2R38 genotype is correlated with sinonasal quality of life in homozygous ΔF508 cystic fibrosis patients. Int. Forum Allergy Rhinol. 6:356-361. http://dx.doi.org /10.1002 /alr .21675
5. Ahlman, H., and O. Nilsson. 2001. The gut as the largest endocrine organ in the body. Ann. Oncol. 12(Suppl 2):S63-S68. http://dx.doi.org /10.1093 /annonc /12 .suppl 2 .S63
6. Akao, H., E. Polisecki, K. Kajinami, S. Trompet, M. Robertson, I. Ford, J.W. Jukema, A.J. de Craen, R.G. Westendorp, J. Shepherd, et al. 2012. KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly. Atherosclerosis. 220:456-462. http://dx.doi.org /10.1016 /j .atherosclerosis .2011 .11 .037
7. Amjadi, F., E. Salehi, M. Mehdizadeh, and R. Aflatoonian. 2014. Role of the innate immunity in female reproductive tract. Adv. Biomed. Res. 3. http://dx.doi.org /10.4103 /2277 -9175 .124626
8. An, S.S., W.C. Wang, C.J. Koziol-White, K. Ahn, D.Y. Lee, R.C. Kurten, R.A. Panettieri Jr., and S.B. Liggett. 2012. TAS2R activation promotes airway smooth muscle relaxation despite ß2-adrenergic receptor tachyphylaxis. Am. J. Physiol. Lung Cell. Mol. Physiol. 303:L304-L311. http://dx.doi.org /10.1152 /ajplung .00126 .2012
9. Ansoleaga, B., P. Garcia-Esparcia, R. Pinacho, J.M. Haro, B. Ramos, and I. Ferrer. 2015. Decrease in olfactory and taste receptor expression in the dorsolateral prefrontal cortex in chronic schizophrenia. J. Psychiatr. Res. 60:109-116. http://dx.doi.org /10.1016 /j .jpsychires .2014 .09 .012
10. Avau, B., A. Rotondo, T. Thijs, C.N. Andrews, P. Janssen, J. Tack, and I. Depoortere. 2015. Targeting extra-oral bitter taste receptors modulates gastrointestinal motility with effects on satiation. Sci. Rep. 5. http://dx.doi.org /10.1038 /srep15985
11. Avila, M., D.M. Ojcius, and O. Yilmaz. 2009. The oral microbiota: living with a permanent guest. DNA Cell Biol. 28:405-411. http:// dx .doi .org /10.1089 /dna .2009 .0874
12. Behrens, M., J. Bartelt, C. Reichling, M. Winnig, C. Kuhn, and W. Meyerhof. 2006. Members of RTP and REEP gene families influence functional bitter taste receptor expression. J. Biol. Chem. 281:20650-20659. http://dx.doi.org /10.1074 /jbc .M513637200
13. Bezençon, C., A. Fürholz, F. Raymond, R. Mansourian, S. Métairon, J. Le Coutre, and S. Damak. 2008. Murine intestinal cells expressing Trpm5 are mostly brush cells and express markers of neuronal and inflammatory cells. J. Comp. Neurol. 509:514-525. http://dx.doi.org /10.1002 /cne .21768
14. Brockhoff, A., M. Behrens, N. Roudnitzky, G. Appendino, C. Avonto, and W. Meyerhof. 2011. Receptor agonism and antagonism of dietary bitter compounds. J. Neurosci. 31:14775-14782. http://dx.doi.org /10.1523 /JNE URO SCI .2923 -11 .2011
15. Bufe, B., P.A. Breslin, C. Kuhn, D.R. Reed, C.D. Tharp, J.P. Slack, U.K. Kim, D. Drayna, and W. Meyerhof. 2005. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception. Curr. Biol. 15:322-327. http://dx.doi.org /10.1016 /j .cub .2005 .01 .047
16. 2+]i mobilization, hyperpolarization, and relaxation of human airway smooth muscle cells. PLoS One. 10. http://dx.doi.org /10.1371 /journal .pone .0131582
17. Campa, D., F. De Rango, M. Carrai, P. Crocco, A. Montesanto, F. Canzian, G. Rose, C. Rizzato, G. Passarino, and R. Barale. 2012. Bitter taste receptor polymorphisms and human aging. PLoS One. 7. http://dx.doi.org /10.1371 /journal .pone .0045232
18. Campbell, M.C., A. Ranciaro, D. Zinshteyn, R. Rawlings-Goss, J. Hirbo, S. Thompson, D. Woldemeskel, A. Froment, J.B. Rucker, S.A. Omar, et al. 2014. Origin and differential selection of allelic variation at TAS2R16 associated with salicin bitter taste sensitivity in Africa. Mol. Biol. Evol. 31:288-302. http://dx.doi.org /10.1093 /molbev /mst211
19. Carrai, M., V. Steinke, P. Vodicka, B. Pardini, N. Rahner, E. Holinski- Feder, M. Morak, H.K. Schackert, H. Görgens, S. Stemmler, et al. 2011. Association between TAS2R38 gene polymorphisms and colorectal cancer risk: a case-control study in two independent populations of Caucasian origin. PLoS One. 6. http://dx.doi.org /10.1371 /journal .pone .0020464
20. Chandrashekar, J., K.L. Mueller, M.A. Hoon, E. Adler, L. Feng, W. Guo, C.S. Zuker, and N.J. Ryba. 2000. T2Rs function as bitter taste receptors. Cell. 100:703-711. http://dx.doi.org /10.1016 /S0092 -8674(00)80706 -0
21. Chandrashekar, J., M.A. Hoon, N.J. Ryba, and C.S. Zuker. 2006. The receptors and cells for mammalian taste. Nature. 444:288-294. http://dx.doi.org /10.1038 /nature05401
22. Chaplin, D.D. 2010. Overview of the immune response. J. Allergy Clin. Immunol. 125(2, Suppl 2):S3-S23. http://dx.doi.org /10.1016 /j .jaci .2009 .12 .980
23. Chaudhari, N., and S.D. Roper. 2010. The cell biology of taste. J. Cell Biol. 190:285-296. (published erratum appears in J. Cell Biol. 2010. 191:429) http://dx.doi.org /10.1083 /jcb .201003144
24. 2+ signaling and CCK release in enteroendocrine STC-1 cells: role of l-type voltage-sensitive Ca2+ channels. Am. J. Physiol. Cell Physiol. 291:C726-C739. http://dx.doi.org /10.1152/ajpcell .00003 .2006
25. Clark, A.A., S.B. Liggett, and S.D. Munger. 2012. Extraoral bitter taste receptors as mediators of off-target drug effects. FAS EB J. 26:4827-4831. http://dx.doi.org /10.1096 /fj .12 -215087
26. Clark, A.A., C.D. Dotson, A.E. Elson, A. Voigt, U. Boehm, W. Meyerhof, N.I. Steinle, and S.D. Munger. 2015. TAS2R bitter taste receptors regulate thyroid function. FAS EB J. 29:164-172. http:// dx .doi .org /10.1096 /fj .14 -262246
27. Csont, T., Z. Murlasits, D. Ménesi, J.Z. Kelemen, P. Bencsik, M. Pipicz, V. Fekete, Á. Zvara, L.G. Puskás, and P. Ferdinandy. 2015. Tissue-specific gene expression in rat hearts and aortas in a model of vascular nitrate tolerance. J. Cardiovasc. Pharmacol. 65:485-493. http://dx.doi.org /10.1097 /FJC .0000000000000218
28. Cui, W., D.D. Taub, and K. Gardner. 2007. qPrimerDepot: a primer database for quantitative real time PCR. Nucleic Acids Res. 35(Database):D805-D809. http://dx.doi.org /10 .1093 /nar / gkl767
29. Cummings, D.E., and J. Overduin. 2007. Gastrointestinal regulation of food intake. J. Clin. Invest. 117:13-23. http://dx.doi.org /10 .1172 /JCI30227
30. Davies, D.G., M.R. Parsek, J.P. Pearson, B.H. Iglewski, J.W. Costerton, and E.P. Greenberg. 1998. The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science. 280:295-298. http://dx.doi.org /10 .1126 /science .280 .5361 .295 Deckmann, K., K. Filipski, G. Krasteva-Christ, M. Fronius, M.
31. Deckmann, K., K. Filipski, G. Krasteva-Christ, M. Fronius, M. Althaus, A. Rafiq, T. Papadakis, L. Renno, I. Jurastow, L. Wessels, et al. 2014. Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes. Proc. Natl. Acad. Sci. USA. 111:8287-8292. http://dx.doi.org /10 .1073 /pnas .1402436111
32. Dehkordi, O., J.E. Rose, M. Fatemi, J.S. Allard, K.V. Balan, J.K. Young, S. Fatima, R.M. Millis, and A. Jayam-Trouth. 2012. Neuronal expression of bitter taste receptors and downstream signaling molecules in the rat brainstem. Brain Res. 1475:1-10. http://dx.doi.org /10 .1016 /j .brainres .2012 .07 .038
33. Deshpande, D.A., W.C. Wang, E.L. McIlmoyle, K.S. Robinett, R.M. Schillinger, S.S. An, J.S. Sham, and S.B. Liggett. 2010. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat. Med. 16:1299- 1304. http://dx.doi.org /10 .1038 /nm .2237
34. Dewhirst, F.E., T. Chen, J. Izard, B.J. Paster, A.C. Tanner, W.H. Yu, A. Lakshmanan, and W.G. Wade. 2010. The human oral microbiome. J. Bacteriol. 192:5002-5017. http://dx.doi.org /10 .1128 /JB .00542 -10
35. Dotson, C.D., L. Zhang, H. Xu, Y.K. Shin, S. Vigues, S.H. Ott, A.E. Elson, H.J. Choi, H. Shaw, J.M. Egan, et al. 2008. Bitter taste receptors influence glucose homeostasis. PLoS One. 3. http://dx.doi.org /10 .1371 /journal .pone .0003974
36. Eberhard, A., A.L. Burlingame, C. Eberhard, G.L. Kenyon, K.H. Nealson, and N.J. Oppenheimer. 1981. Structural identification of autoinducer of Photobacterium fischeri luciferase. Biochemistry. 20:2444-2449. http://dx.doi.org /10 .1021 /bi00512a013
37. Finger, T.E., B. Böttger, A. Hansen, K.T. Anderson, H. Alimohammadi, and W.L. Silver. 2003. Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration. Proc. Natl. Acad. Sci. USA. 100:8981-8986. http://dx.doi.org /10 .1073 /pnas .1531172100
38. Finger, T.E., V. Danilova, J. Barrows, D.L. Bartel, A.J. Vigers, L. Stone, G. Hellekant, and S.C. Kinnamon. 2005. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science. 310:1495-1499. http://dx.doi.org /10 .1126 /science .1118435
39. Foster, S.R., E.R. Porrello, B. Purdue, H.W. Chan, A. Voigt, S. Frenzel, R.D. Hannan, K.M. Moritz, D.G. Simmons, P. Molenaar, et al. 2013. Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart. PLoS One. 8. http://dx.doi.org /10 .1371 /journal .pone .0064579
40. Foster, S.R., K. Blank, L.E. See Hoe, M. Behrens, W. Meyerhof, J.N. Peart, and W.G. Thomas. 2014a. Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart. FAS EB J. 28:4497-4508. http://dx.doi.org /10 .1096 /fj .14 -256305
41. Foster, S.R., E. Roura, and W.G. Thomas. 2014b. Extrasensory perception: odorant and taste receptors beyond the nose and mouth. Pharmacol. Ther. 142:41-61. http://dx.doi.org /10 .1016 /j .pharmthera .2013 .11 .004
42. Foster, S.R., E.R. Porrello, M. Stefani, N.J. Smith, P. Molenaar, C.G. dos Remedios, W.G. Thomas, and M. Ramialison. 2015. Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation. Naunyn Schmiedebergs Arch. Pharmacol. 388:1009-1027. http://dx.doi.org /10 .1007 /s00210 -015 -1118 -1
43. Gaida, M.M., U. Dapunt, and G.M. Hänsch. 2016a. Sensing developing biofilms: the bitter receptor T2R38 on myeloid cells. Pathog. Dis. 74. http://dx.doi.org /10 .1093 /femspd /ftw004
44. Gaida, M.M., C. Mayer, U. Dapunt, S. Stegmaier, P. Schirmacher, G.H. Wabnitz, and G.M. Hänsch. 2016b. Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. Oncotarget. 7:12623-12632.
45. Gallo, S., S. Grossi, G. Montrasio, G. Binelli, R. Cinquetti, D. Simmen, P. Castelnuovo, and P. Campomenosi. 2016. TAS2R38 taste receptor gene and chronic rhinosinusitis: new data from an Italian population. BMC Med. Genet. 17. http://dx.doi.org /10 .1186 /s12881 -016 -0321 -3
46. Garcia-Esparcia, P., A. Schlüter, M. Carmona, J. Moreno, B. Ansoleaga, B. Torrejón-Escribano, S. Gustincich, A. Pujol, and I. Ferrer. 2013. Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain. J. Neuropathol. Exp. Neurol. 72:524-539. http://dx.doi.org /10 .1097 /NEN .0b013e318294fd76
47. Gerbe, F., E. Sidot, D.J. Smyth, M. Ohmoto, I. Matsumoto, V. Dardalhon, P. Cesses, L. Garnier, M. Pouzolles, B. Brulin, et al. 2016. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature. 529:226-230. http://dx.doi.org /10 .1038 /nature16527
48. Gil, S., S. Coldwell, J.L. Drury, F. Arroyo, T. Phi, S. Saadat, D. Kwong, and W.O. Chung. 2015. Genotype-specific regulation of oral innate immunity by T2R38 taste receptor. Mol. Immunol. 68(2, 2 Pt C):663-670. http://dx.doi.org /10 .1016 /j .molimm .2015 .10 .012
49. Grassin-Delyle, S., C. Abrial, S. Fayad-Kobeissi, M. Brollo, C. Faisy, J.C. Alvarez, E. Naline, and P. Devillier. 2013. The expression and relaxant effect of bitter taste receptors in human bronchi. Respir. Res. 14. http://dx.doi.org /10 .1186 /1465 -9921 -14 -134
50. Greene, T.A., S. Alarcon, A. Thomas, E. Berdougo, B.J. Doranz, P.A. Breslin, and J.B. Rucker. 2011. Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One. 6. http://dx.doi.org /10 .1371 /journal .pone .0020123
51. Gribble, F.M., and F. Reimann. 2016. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu. Rev. Physiol. 78:277-299. http://dx.doi.org /10 .1146 /annurev -physiol -021115 -105439
52. Gulbransen, B.D., T.R. Clapp, T.E. Finger, and S.C. Kinnamon. 2008. Nasal solitary chemoreceptor cell responses to bitter and trigeminal stimulants in vitro. J. Neurophysiol. 99:2929-2937. http://dx.doi.org /10.1152 /jn .00066 .2008
53. Harmston, N., and B. Lenhard. 2013. Chromatin and epigenetic features of long-range gene regulation. Nucleic Acids Res. 41:7185- 7199. http://dx.doi.org /10 .1093 /nar /gkt499
54. Hass, N., K. Schwarzenbacher, and H. Breer. 2007. A cluster of gustducin-expressing cells in the mouse stomach associated with two distinct populations of enteroendocrine cells. Histochem. Cell Biol. 128:457-471. http://dx.doi.org /10 .1007 /s00418 -007 -0325 -3
55. Heinz, S., C.E. Romanoski, C. Benner, and C.K. Glass. 2015. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16:144-154. http://dx.doi.org /10 .1038 /nrm3949
56. Höfer, D., B. Püschel, and D. Drenckhahn. 1996. Taste receptor-like cells in the rat gut identified by expression of a-gustducin. Proc. Natl. Acad. Sci. USA. 93:6631-6634. http://dx.doi.org /10 .1073 / pnas .93 .13 .6631
57. Howitt, M.R., S. Lavoie, M. Michaud, A.M. Blum, S.V. Tran, J.V. Weinstock, C.A. Gallini, K. Redding, R.F. Margolskee, L.C. Osborne, et al. 2016. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science. 351:1329- 1333. http://dx.doi.org /10 .1126 /science .aaf1648
58. Huang, L., Y.G. Shanker, J. Dubauskaite, J.Z. Zheng, W. Yan, S. Rosenzweig, A.I. Spielman, M. Max, and R.F. Margolskee. 1999. Gγ13 colocalizes with gustducin in taste receptor cells and mediates IP3 responses to bitter denatonium. Nat. Neurosci. 2:1055-1062. http://dx.doi.org /10 .1038 /15981
59. Ilegems, E., K. Iwatsuki, Z. Kokrashvili, O. Benard, Y. Ninomiya, and R.F. Margolskee. 2010. REEP2 enhances sweet receptor function by recruitment to lipid rafts. J. Neurosci. 30:13774-13783. http:// dx .doi .org /10 .1523 /JNE URO SCI .0091 -10 .2010
60. Jang, H.J., Z. Kokrashvili, M.J. Theodorakis, O.D. Carlson, B.J. Kim, J. Zhou, H.H. Kim, X. Xu, S.L. Chan, M. Juhaszova, et al. 2007. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc. Natl. Acad. Sci. USA. 104:15069- 15074. http://dx.doi.org /10 .1073 /pnas .0706890104
61. Janssen, S., J. Laermans, P.J. Verhulst, T. Thijs, J. Tack, and I. Depoortere. 2011. Bitter taste receptors and a-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. Proc. Natl. Acad. Sci. USA. 108:2094-2099. http://dx.doi.org /10 .1073 /pnas .1011508108
62. Jeon, T.I., B. Zhu, J.L. Larson, and T.F. Osborne. 2008. SRE BP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice. J. Clin. Invest. 118:3693-3700. http:// dx .doi .org /10 .1172 /JCI36461
63. Jeon, T.I., Y.K. Seo, and T.F. Osborne. 2011. Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK. Biochem. J. 438:33-37. http://dx.doi.org /10 .1042 /BJ20110009
64. Ji, M., X. Su, X. Su, Y. Chen, W. Huang, J. Zhang, Z. Gao, C. Li, and X. Lu. 2014. Identification of novel compounds for human bitter taste receptors. Chem. Biol. Drug Des. 84:63-74. http://dx.doi.org /10 .1111 /cbdd .12293
65. Kaji, I., S. Karaki, Y. Fukami, M. Terasaki, and A. Kuwahara. 2009. Secretory effects of a luminal bitter tastant and expressions of bitter taste receptors, T2Rs, in the human and rat large intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 296:G971-G981. http:// dx .doi .org /10.1152 /ajpgi .90514 .2008
66. Kautiainen, A. 1992. Determination of hemoglobin adducts from aldehydes formed during lipid peroxidation in vitro. Chem. Biol. Interact. 83:55-63. http://dx.doi.org /10 .1016 /0009 -2797(92)90091 -X
67. Keller, M., X. Liu, T. Wohland, K. Rohde, M.T. Gast, M. Stumvoll, P. Kovacs, A. Tönjes, and Y. Böttcher. 2013. TAS2R38 and its influence on smoking behavior and glucose homeostasis in the German Sorbs. PLoS One. 8. http://dx.doi.org /10 .1371 /journal .pone .0080512
68. Kim, K.S., J.M. Egan, and H.J. Jang. 2014. Denatonium induces secretion of glucagon-like peptide-1 through activation of bitter taste receptor pathways. Diabetologia. 57:2117-2125. (published erratum appears in Diabetologia. 2014. 57:2428) http://dx.doi.org /10 .1007 /s00125 -014 -3326 -5
69. Kim, U.K., E. Jorgenson, H. Coon, M. Leppert, N. Risch, and D. Drayna. 2003. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide. Science. 299:1221-1225. http://dx.doi.org /10 .1126 /science .1080190
70. Krasteva, G., B.J. Canning, P. Hartmann, T.Z. Veres, T. Papadakis, C. Mühlfeld, K. Schliecker, Y.N. Tallini, A. Braun, H. Hackstein, et al. 2011. Cholinergic chemosensory cells in the trachea regulate breathing. Proc. Natl. Acad. Sci. USA. 108:9478-9483. http://dx.doi.org /10 .1073 /pnas .1019418108
71. Krasteva, G., B.J. Canning, T. Papadakis, and W. Kummer. 2012a. Cholinergic brush cells in the trachea mediate respiratory responses to quorum sensing molecules. Life Sci. 91:992-996. http://dx.doi.org /10 .1016 /j .lfs .2012 .06 .014
72. Krasteva, G., P. Hartmann, T. Papadakis, M. Bodenbenner, L. Wessels, E. Weihe, B. Schütz, A.C. Langheinrich, V. Chubanov, T. Gudermann, et al. 2012b. Cholinergic chemosensory cells in the auditory tube. Histochem. Cell Biol. 137:483-497. http://dx.doi.org /10 .1007 /s00418 -012 -0911 -x
73. Krasteva-Christ, G., A. Soultanova, B. Schütz, T. Papadakis, C. Weiss, K. Deckmann, V. Chubanov, T. Gudermann, A. Voigt, W. Meyerhof, et al. 2015. Identification of cholinergic chemosensory cells in mouse tracheal and laryngeal glandular ducts. Int. Immunopharmacol. 29:158-165. http://dx.doi.org /10 .1016 /j .intimp .2015 .05 .028
74. Latorre, R., J. Huynh, M. Mazzoni, A. Gupta, E. Bonora, P. Clavenzani, L. Chang, E.A. Mayer, R. De Giorgio, and C. Sternini. 2016. Expression of the bitter taste receptor, T2R38, in enteroendocrine cells of the colonic mucosa of overweight/ obese vs. lean subjects. PLoS One. 11. http://dx.doi.org /10 .1371 /journal .pone .0147468
75. Lee, R.J., and N.A. Cohen. 2013. The emerging role of the bitter taste receptor T2R38 in upper respiratory infection and chronic rhinosinusitis. Am. J. Rhinol. Allergy. 27:283-286. http://dx.doi.org /10 .2500 /ajra .2013 .27 .3911
76. Lee, R.J., and N.A. Cohen. 2014. Bitter and sweet taste receptors in the respiratory epithelium in health and disease. J. Mol. Med. 92:1235-1244. http://dx.doi.org /10 .1007 /s00109 -014 -1222 -6
77. Lee, R.J., G. Xiong, J.M. Kofonow, B. Chen, A. Lysenko, P. Jiang, V. Abraham, L. Doghramji, N.D. Adappa, J.N. Palmer, et al. 2012. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J. Clin. Invest. 122:4145-4159. http://dx.doi.org /10 .1172 /JCI64240
78. Lee, R.J., B. Chen, K.M. Redding, R.F. Margolskee, and N.A. Cohen. 2014a. Mouse nasal epithelial innate immune responses to Pseudomonas aeruginosa quorum-sensing molecules require taste signaling components. Innate Immun. 20:606-617. http:// dx .doi .org /10 .1177 /1753425913503386
79. Lee, R.J., J.M. Kofonow, P.L. Rosen, A.P. Siebert, B. Chen, L. Doghramji, G. Xiong, N.D. Adappa, J.N. Palmer, D.W. Kennedy, et al. 2014b. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Invest. 124:1393-1405. http://dx.doi.org /10 .1172 /JCI72094
80. Le Nevé, B., M. Foltz, H. Daniel, and R. Gouka. 2010. The steroid glycoside H.g.-12 from Hoodia gordonii activates the human bitter receptor TAS2R14 and induces CCK release from HuTu-80 cells. Am. J. Physiol. Gastrointest. Liver Physiol. 299:G1368-G1375. http://dx.doi.org /10.1152 /ajpgi .00135 .2010
81. Levit, A., S. Nowak, M. Peters, A. Wiener, W. Meyerhof, M. Behrens, and M.Y. Niv. 2014. The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14. FAS EB J. 28:1181-1197. http://dx.doi.org /10 .1096 /fj .13 -242594
82. Li, F., and M. Zhou. 2012. Depletion of bitter taste transduction leads to massive spermatid loss in transgenic mice. Mol. Hum. Reprod. 18:289-297. http://dx.doi.org /10 .1093 /molehr /gas005
83. Li, H., A.J. Pakstis, J.R. Kidd, and K.K. Kidd. 2011. Selection on the human bitter taste gene, TAS2R16, in Eurasian populations. Hum. Biol. 83:363-377. http://dx.doi.org /10 .3378 /027 .083 .0303
84. Lin, W., T. Ogura, R.F. Margolskee, T.E. Finger, and D. Restrepo. 2008. TRPM5-expressing solitary chemosensory cells respond to odorous irritants. J. Neurophysiol. 99:1451-1460. http://dx.doi.org /10.1152 /jn .01195 .2007
85. Liu, X., F. Gu, L. Jiang, F. Chen, and F. Li. 2015. Expression of bitter taste receptor Tas2r105 in mouse kidney. Biochem. Biophys. Res. Commun. 458:733-738. http://dx.doi.org /10 .1016 /j .bbrc .2015 .01 .089
86. Lossow, K., S. Hübner, N. Roudnitzky, J.P. Slack, F. Pollastro, M. Behrens, and W. Meyerhof. 2016. Comprehensive analysis of mouse bitter taste receptors reveals different molecular receptive ranges for orthologous receptors in mice and humans. J. Biol. Chem. 291:15358-15377. http://dx.doi.org /10 .1074 /jbc .M116 .718544
87. Lund, T.C., A.J. Kobs, A. Kramer, M. Nyquist, M.T. Kuroki, J. Osborn, D.S. Lidke, S.T. Low-Nam, B.R. Blazar, and J. Tolar. 2013. Bone marrow stromal and vascular smooth muscle cells have chemosensory capacity via bitter taste receptor expression. PLoS One. 8. http://dx.doi.org /10 .1371 /journal .pone .0058945
88. Malki, A., J. Fiedler, K. Fricke, I. Ballweg, M.W. Pfaffl, and D. Krautwurst. 2015. Class I odorant receptors, TAS1R and TAS2R taste receptors, are markers for subpopulations of circulating leukocytes. J. Leukoc. Biol. 97:533-545. http://dx.doi.org /10 .1189 /jlb .2A0714 -331RR
89. Manson, M.L., J. Säfholm, M. Al-Ameri, P. Bergman, A.C. Orre, K. Swärd, A. James, S.E. Dahlén, and M. Adner. 2014. Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle. Eur. J. Pharmacol. 740:302-311. http:// dx .doi .org /10 .1016 /j .ejphar .2014 .07 .005
90. Marx, V. 2014. Cell communication: stop the microbial chatter. Nature. 511:493-497. http://dx.doi.org /10 .1038 /511493a
91. Maurer, S., G.H. Wabnitz, N.A. Kahle, S. Stegmaier, B. Prior, T. Giese, M.M. Gaida, Y. Samstag, and G.M. Hänsch. 2015. Tasting Pseudomonas aeruginosa biofilms: human neutrophils express the bitter receptor T2R38 as sensor for the quorum sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone. Front. Immunol. 6. http://dx.doi.org /10 .3389 /fimmu .2015 .00369
92. McLaughlin, S.K., P.J. McKinnon, and R.F. Margolskee. 1992. Gustducin is a taste-cell-specific G protein closely related to the transducins. Nature. 357:563-569. http://dx.doi.org /10 .1038 /357563a0
93. Meyerhof, W., C. Batram, C. Kuhn, A. Brockhoff, E. Chudoba, B. Bufe, G. Appendino, and M. Behrens. 2010. The molecular receptive ranges of human TAS2R bitter taste receptors. Chem. Senses. 35:157-170. http://dx.doi.org /10 .1093 /chemse /bjp092
94. Mueller, K.L., M.A. Hoon, I. Erlenbach, J. Chandrashekar, C.S. Zuker, and N.J. Ryba. 2005. The receptors and coding logic for bitter taste. Nature. 434:225-229. http://dx.doi.org /10 .1038 / nature03352
95. Nealson, K.H., and J.W. Hastings. 1979. Bacterial bioluminescence: its control and ecological significance. Microbiol. Rev. 43:496-518.
96. Nealson, K.H., T. Platt, and J.W. Hastings. 1970. Cellular control of the synthesis and activity of the bacterial luminescent system. J. Bacteriol. 104:313-322.
97. Ogura, T., K. Krosnowski, L. Zhang, M. Bekkerman, and W. Lin. 2010. Chemoreception regulates chemical access to mouse vomeronasal organ: role of solitary chemosensory cells. PLoS One. 5. http://dx.doi.org /10 .1371 /journal .pone .0011924
98. Orsmark-Pietras, C., A. James, J.R. Konradsen, B. Nordlund, C. Söderhäll, V. Pulkkinen, C. Pedroletti, K. Daham, M. Kupczyk, B. Dahlén, et al. 2013. Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics. Eur. Respir. J. 42:65- 78. http://dx.doi.org /10 .1183 /09031936 .00077712
99. Panneck, A.R., A. Rafiq, B. Schütz, A. Soultanova, K. Deckmann, V. Chubanov, T. Gudermann, E. Weihe, G. Krasteva-Christ, V. Grau, et al. 2014. Cholinergic epithelial cell with chemosensory traits in murine thymic medulla. Cell Tissue Res. 358:737-748. http://dx.doi.org /10 .1007 /s00441 -014 -2002 -x
100. Pastorelli, L., C. De Salvo, J.R. Mercado, M. Vecchi, and T.T. Pizarro. 2013. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front. Immunol. 4. http://dx.doi.org /10 .3389 /fimmu .2013 .00280
101. Peng, Y., S. Gillis-Smith, H. Jin, D. Tränkner, N.J. Ryba, and C.S. Zuker. 2015. Sweet and bitter taste in the brain of awake behaving animals. Nature. 527:512-515. http://dx.doi.org /10 .1038 / nature15763
102. Peterson, L.W., and D. Artis. 2014. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14:141-153. http://dx.doi.org /10 .1038 /nri3608
103. Prandi, S., M. Bromke, S. Hübner, A. Voigt, U. Boehm, W. Meyerhof, and M. Behrens. 2013. A subset of mouse colonic goblet cells expresses the bitter taste receptor Tas2r131. PLoS One. 8. http:// dx .doi .org /10 .1371 /journal .pone .0082820
104. Psichas, A., F. Reimann, and F.M. Gribble. 2015. Gut chemosensing mechanisms. J. Clin. Invest. 125:908-917. http://dx.doi.org /10 .1172 /JCI76309
105. Pulkkinen, V., M.L. Manson, J. Säfholm, M. Adner, and S.E. Dahlén. 2012. 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. http://dx.doi.org /10.1152 /ajplung .00205 .2012
106. Pydi, S.P., T. Sobotkiewicz, R. Billakanti, R.P. Bhullar, M.C. Loewen, and P. Chelikani. 2014. Amino acid derivatives as bitter taste receptor (T2R) blockers. J. Biol. Chem. 289:25054-25066. http:// dx .doi .org /10 .1074 /jbc .M114 .576975
107. Pydi, S.P., A. Jaggupilli, K.M. Nelson, S.R. Abrams, R.P. Bhullar, M.C. Loewen, and P. Chelikani. 2015. Abscisic acid acts as a blocker of the bitter taste G protein-coupled receptor T2R4. Biochemistry. 54:2622-2631. http://dx.doi.org /10 .1021 /acs .biochem .5b00265
108. Rajkumar, P., W.H. Aisenberg, O.W. Acres, R.J. Protzko, and J.L. Pluznick. 2014. Identification and characterization of novel renal sensory receptors. PLoS One. 9. http://dx.doi.org /10 .1371 / journal .pone .0111053
109. Raz, T., P. Kapranov, D. Lipson, S. Letovsky, P.M. Milos, and J.F. Thompson. 2011. Protocol dependence of sequencing-based gene expression measurements. PLoS One. 6. http://dx.doi.org /10 .1371 /journal .pone .0019287
110. Risso, D., S. Tofanelli, G. Morini, D. Luiselli, and D. Drayna. 2014. Genetic variation in taste receptor pseudogenes provides evidence for a dynamic role in human evolution. BMC Evol. Biol. 14. http://dx.doi.org /10 .1186 /s12862 -014 -0198 -8
111. Robinett, K.S., D.A. Deshpande, M.M. Malone, and S.B. Liggett. 2011. Agonist-promoted homologous desensitization of human airway smooth muscle bitter taste receptors. Am. J. Respir. Cell Mol. Biol. 45:1069-1074. http://dx.doi.org /10 .1165 /rcmb .2011 -0061OC
112. Robinett, K.S., C.J. Koziol-White, A. Akoluk, S.S. An, R.A. Panettieri Jr., and S.B. Liggett. 2014. Bitter taste receptor function in asthmatic and nonasthmatic human airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 50:678-683. http://dx.doi.org /10 .1165 /rcmb .2013 -0439RC
113. Roland, W.S., R.J. Gouka, H. Gruppen, M. Driesse, L. van Buren, G. Smit, and J.P. Vincken. 2014. 6-methoxyflavanones as bitter taste receptor blockers for hTAS2R39. PLoS One. 9. http://dx.doi.org /10 .1371 /journal .pone .0094451
114. Salathe, M. 2007. Regulation of mammalian ciliary beating. Annu. Rev. Physiol. 69:401-422. http://dx.doi.org /10 .1146 /annurev .physiol .69 .040705 .141253
115. Saunders, C.J., M. Christensen, T.E. Finger, and M. Tizzano. 2014. Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation. Proc. Natl. Acad. Sci. USA. 111:6075-6080. http://dx.doi.org /10 .1073 /pnas .1402251111
116. Shah, A.S., Y. Ben-Shahar, T.O. Moninger, J.N. Kline, and M.J. Welsh. 2009. Motile cilia of human airway epithelia are chemosensory. Science. 325:1131-1134. http://dx.doi.org /10 .1126 /science .1173869
117. Shaykhiev, R., and R.G. Crystal. 2013. Innate immunity and chronic obstructive pulmonary disease: a mini-review. Gerontology. 59:481- 489. http://dx.doi.org /10 .1159 /000354173
118. Shi, P., J. Zhang, H. Yang, and Y.P. Zhang. 2003. Adaptive diversification of bitter taste receptor genes in mammalian evolution. Mol. Biol. Evol. 20:805-814. http://dx.doi.org /10 .1093 /molbev /msg083
119. Shiffman, D., E.S. O'Meara, L.A. Bare, C.M. Rowland, J.Z. Louie, A.R. Arellano, T. Lumley, K. Rice, O. Iakoubova, M.M. Luke, et al. 2008. Association of gene variants with incident myocardial infarction in the cardiovascular health study. Arterioscler. Thromb. Vasc. Biol. 28:173-179. http://dx.doi.org /10.1161 /ATV BAHA .107 .153981
120. Singh, N., M. Vrontakis, F. Parkinson, and P. Chelikani. 2011. Functional bitter taste receptors are expressed in brain cells. Biochem. Biophys. Res. Commun. 406:146-151. http://dx.doi.org /10.1016 /j .bbrc .2011 .02 .016
121. Singh, N., R. Chakraborty, R.P. Bhullar, and P. Chelikani. 2014. Differential expression of bitter taste receptors in non-cancerous breast epithelial and breast cancer cells. Biochem. Biophys. Res. Commun. 446:499-503. http://dx.doi.org /10.1016 /j .bbrc .2014 .02 .140
122. Slack, J.P., A. Brockhoff, C. Batram, S. Menzel, C. Sonnabend, S. Born, M.M. Galindo, S. Kohl, S. Thalmann, L. Ostopovici-Halip, et al. 2010. Modulation of bitter taste perception by a small molecule hTAS2R antagonist. Curr. Biol. 20:1104-1109. http:// dx .doi .org /10.1016 /j .cub .2010 .04 .043
123. Sommer, F., and F. Bäckhed. 2013. The gut microbiota--masters of host development and physiology. Nat. Rev. Microbiol. 11:227-238. http://dx.doi.org /10.1038 /nrmicro2974
124. Soultanova, A., A. Voigt, V. Chubanov, T. Gudermann, W. Meyerhof, U. Boehm, and W. Kummer. 2015. Cholinergic chemosensory cells of the thymic medulla express the bitter receptor Tas2r131. Int. Immunopharmacol. 29:143-147. http://dx.doi.org /10.1016 /j .intimp .2015 .06 .005
125. Suh, H.W., K.B. Lee, K.S. Kim, H.J. Yang, E.K. Choi, M.H. Shin, Y.S. Park, Y.C. Na, K.S. Ahn, Y.P. Jang, et al. 2015. A bitter herbal medicine Gentiana scabra root extract stimulates glucagon-like peptide-1 secretion and regulates blood glucose in db/db mouse. J. Ethnopharmacol. 172:219-226. http://dx.doi.org /10.1016 /j .jep .2015 .06 .042
126. Tan, X., and M.J. Sanderson. 2014. Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity. Br. J. Pharmacol. 171:646-662. http://dx.doi.org /10.1111 /bph .12460
127. Taruno, A., V. Vingtdeux, M. Ohmoto, Z. Ma, G. Dvoryanchikov, A. Li, L. Adrien, H. Zhao, S. Leung, M. Abernethy, et al. 2013. CAL HM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature. 495:223-226. http://dx.doi.org /10.1038 /nature11906
128. Tazzeo, T., G. Bates, H.N. Roman, A.M. Lauzon, M.D. Khasnis, M. Eto, and L.J. Janssen. 2012. Caffeine relaxes smooth muscle through actin depolymerization. Am. J. Physiol. Lung Cell. Mol. Physiol. 303:L334-L342. http://dx.doi.org /10.1152 /ajplung .00103 .2012
129. Tizzano, M., B.D. Gulbransen, A. Vandenbeuch, T.R. Clapp, J.P. Herman, H.M. Sibhatu, M.E. Churchill, W.L. Silver, S.C. Kinnamon, and T.E. Finger. 2010. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc. Natl. Acad. Sci. USA. 107:3210-3215. http://dx.doi.org /10.1073 / pnas .0911934107
130. Tomás, J., C.R. Santos, T. Quintela, and I. Gonçalves. 2016. "Tasting" the cerebrospinal fluid: another function of the choroid plexus? Neuroscience. 320:160-171. http://dx.doi.org /10.1016 /j .neuroscience .2016 .01 .057
131. Ueda, T., S. Ugawa, H. Yamamura, Y. Imaizumi, and S. Shimada. 2003. Functional interaction between T2R taste receptors and G-protein a subunits expressed in taste receptor cells. J. Neurosci. 23:7376-7380.
132. Upadhyaya, J.D., N. Singh, A.S. Sikarwar, R. Chakraborty, S.P. Pydi, R.P. Bhullar, S. Dakshinamurti, and P. Chelikani. 2014. Dextromethorphan mediated bitter taste receptor activation in the pulmonary circuit causes vasoconstriction. PLoS One. 9. http://dx.doi.org /10.1371 /journal .pone .0110373
133. Voigt, A., S. Hübner, K. Lossow, I. Hermans-Borgmeyer, U. Boehm, and W. Meyerhof. 2012. Genetic labeling of Tas1r1 and Tas2r131 taste receptor cells in mice. Chem. Senses. 37:897-911. http://dx.doi.org /10 .1093 /chemse /bjs082
134. Voigt, A., S. Hübner, L. Döring, N. Perlach, I. Hermans-Borgmeyer, U. Boehm, and W. Meyerhof. 2015. Cre-mediated recombination in Tas2r131 cells-a unique way to explore bitter taste receptor function inside and outside of the taste system. Chem. Senses. 40:627-639. http://dx.doi.org /10.1093 /chemse /bjv049
135. von Moltke, J., M. Ji, H.E. Liang, and R.M. Locksley. 2016. Tuft-cellderived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature. 529:221-225. http://dx.doi.org /10.1038 / nature16161
136. Wang, H., H. Yang, C.S. Shivalila, M.M. Dawlaty, A.W. Cheng, F. Zhang, and R. Jaenisch. 2013. One-step generation of mice carrying mutations in multiple genes by CRI SPR/Cas-mediated genome engineering. Cell. 153:910-918. http://dx.doi.org /10.1016 /j .cell .2013 .04 .025
137. Wei, M.Y., L. Xue, L. Tan, W.B. Sai, X.C. Liu, Q.J. Jiang, J. Shen, Y.B. Peng, P. Zhao, M.F. Yu, et al. 2015. Involvement of largeconductance Ca2+-activated K+ channels in chloroquine-induced force alterations in pre-contracted airway smooth muscle. PLoS One. 10. http://dx.doi.org /10.1371 /journal .pone .0121566
138. Wendell, S., X. Wang, M. Brown, M.E. Cooper, R.S. DeSensi, R.J. Weyant, R. Crout, D.W. McNeil, and M.L. Marazita. 2010. Taste genes associated with dental caries. J. Dent. Res. 89:1198-1202. http://dx.doi.org /10.1177 /0022034510381502
139. Wölfle, U., F.A. Elsholz, A. Kersten, B. Haarhaus, W.E. Müller, and C.M. Schempp. 2015. Expression and functional activity of the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes. Skin Pharmacol. Physiol. 28:137-146. http://dx.doi.org /10.1159 /000367631
140. Wölfle, U., F.A. Elsholz, A. Kersten, B. Haarhaus, U. Schumacher, and C.M. Schempp. 2016. Expression and functional activity of the human bitter taste receptor TAS2R38 in human placental tissues and JEG-3 cells. Molecules. 21. http://dx.doi.org /10.3390 /molecules21030306
141. Wong, G.T., K.S. Gannon, and R.F. Margolskee. 1996. Transduction of bitter and sweet taste by gustducin. Nature. 381:796-800. http://dx.doi.org /10.1038 /381796a0
142. Workman, A.D., J.N. Palmer, N.D. Adappa, and N.A. Cohen. 2015. The role of bitter and sweet taste receptors in upper irway Immunity. Curr. Allergy Asthma Rep. 15. http://dx.doi.org /10.1007 /s11882 -015 -0571 -8
143. Wu, S.V., N. Rozengurt, M. Yang, S.H. Young, J. Sinnett-Smith, and E. Rozengurt. 2002. Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells. Proc. Natl. Acad. Sci. USA. 99:2392-2397. http://dx.doi.org /10.1073 /pnas .042617699
144. Xu, J., J. Cao, N. Iguchi, D. Riethmacher, and L. Huang. 2013. Functional characterization of bitter-taste receptors expressed in mammalian testis. Mol. Hum. Reprod. 19:17-28. http://dx.doi.org /10.1093 /molehr /gas040
145. Yoshikawa, K., H. Nakagawa, N. Mori, H. Watanabe, and K. Touhara. 2013. An unsaturated aliphatic alcohol as a natural ligand for a mouse odorant receptor. Nat. Chem. Biol. 9:160-162. http://dx.doi.org /10.1038 /nchembio .1164
146. Zhai, K., Z. Yang, X. Zhu, E. Nyirimigabo, Y. Mi, Y. Wang, Q. Liu, L. Man, S. Wu, J. Jin, and G. Ji. 2016. Activation of bitter taste receptors (tas2rs) relaxes detrusor smooth muscle and suppresses overactive bladder symptoms. Oncotarget. 7:21156-21167.
147. Zhang, C.H., C. Chen, L.M. Lifshitz, K.E. Fogarty, M.S. Zhu, and R. ZhuGe. 2012. Activation of BK channels may not be required for bitter tastant-induced bronchodilation. Nat. Med. 18:648-650.
148. Zhang, C.-H., L.M. Lifshitz, K.F. Uy, M. Ikebe, K.E. Fogarty, and R. ZhuGe. 2013. The cellular and molecular basis of bitter tastantinduced bronchodilation. PLoS Biol. 11. (published erratum appears in PLoS Biol. 2013. 11.) http://dx.doi.org /10 1371 / journal .pbio .1001501