Recent advances in structure and function studies on human bitter taste receptors

Current Protein and Peptide Science

Volumn 13, Issue 6, 2012, Pages 501-508

  Pydi, Sai Prasad ^a   Upadhyaya, Jasbir ^a   Singh, Nisha ^a   Bhullar, Rajinder Pal ^a   Chelikani, Prashen ^a,b  

^a UNIVERSITY OF MANITOBA   (Canada)

^b MANITOBA INSTITUTE OF CHILD HEALTH   (Canada)

Author keywords

Bitter blockers; Bitter taste receptors (T2Rs); G protein coupled receptors (GPCRs); Structure function analysis; T2R heterologous expression; T2R ligand binding; T2R receptor activation mechanism(s)

Indexed keywords

AMINO ACID; BITTER TASTE RECEPTOR; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR A; GLUCAGON LIKE PEPTIDE 1; PHENYLTHIOUREA; RECEPTOR ACTIVITY MODIFYING PROTEIN; UNCLASSIFIED DRUG;

ARTICLE; BITTER TASTE; CRYSTAL STRUCTURE; ENZYME ACTIVATION; GENETIC LINKAGE; HETEROLOGOUS EXPRESSION; HUMAN; INTRACELLULAR SIGNALING; LIGAND BINDING; MUTANT; NONHUMAN; PROTEIN EXPRESSION; PROTEIN INTAKE; REGULATORY MECHANISM; SEQUENCE ANALYSIS; SINGLE NUCLEOTIDE POLYMORPHISM; SWEETNESS; TASTE BUD;

ANIMALS; HUMANS; LIGANDS; RECEPTORS, G-PROTEIN-COUPLED;

EID: 84870232467     PISSN: 13892037     EISSN: 18755550     Source Type: Journal    
DOI: 10.2174/138920312803582942     Document Type: Article

References (79)

1. Finger T.E. Cell types and lineages in taste buds. Chem. Senses, 2005, 30 Suppl 1:54-55.
2. Hoon, M.A.; Adler, E.; Lindemeier, J.; Battey, J.F.; Ryba, N.J.; Zuker, C.S. Putative mammalian taste receptors: a class of tastespecific GPCRs with distinct topographic selectivity. Cell, 1999, 96:541-551.
3. Chandrashekar, J.; Mueller, K.L.; Hoon, M.A.; Adler, E.; Feng, L.; Guo, W.; Zuker, C.S.; Ryba, N.J. T2Rs function as bitter taste receptors. Cell, 2000, 100:703-711.
4. Galindo, M.M.; Voigt, N.; Stein, J.; van Lengerich, J.; Raguse, J.D.; Hofmann, T.; Meyerhof, W.; Behrens, M. G protein-coupled receptors in human fat taste perception. Chem. Senses, 2012, 37:123-139.
5. Matsumura, S.; Mizushige, T.; Yoneda, T.; Iwanaga, T.; Tsuzuki, S.; Inoue, K.; Fushiki, T. GPR expression in the rat taste bud relating to fatty acid sensing. Biomed. Res., 2007, 28:49-55.
6. Cartoni, C.; Yasumatsu, K.; Ohkuri, T.; Shigemura, N.; Yoshida, R.; Godinot, N.; le Coutre, J.; Ninomiya, Y.; Damak, S. Taste preference for fatty acids is mediated by GPR40 and GPR120. J. Neurosci., 2010, 30:8376-8382.
7. Temussi, P.A. The good taste of peptides. J. Pept. Sci., 2012, 18:73-82.
8. Conte, C.; Ebeling, M.; Marcuz, A.; Nef, P.; Andres-Barquin, P.J. Identification and characterization of human taste receptor genes belonging to the TAS2R family. Cytogenet. Genome. Res., 2002, 98:45-53.
9. Lagerstrom, M.C.; Schioth, H.B. Structural diversity of G proteincoupled receptors and significance for drug discovery. Nat. Rev. Drug Discov., 2008, 7:339-357.
10. Shi, P.; Zhang, J.; Yang, H.; Zhang, Y.P. Adaptive diversification of bitter taste receptor genes in Mammalian evolution. Mol. Biol. Evol., 2003, 20:805-814.
11. Wang, M.; Yao, Y.; Kuang, D.; Hampson, D.R. Activation of family C G-protein-coupled receptors by the tripeptide glutathione. J. Biol. Chem., 2006, 281:8864-8870.
12. Horn, F.; Bettler, E.; Oliveira, L.; Campagne, F.; Cohen, F.E.; Vriend, G. GPCRDB information system for G protein-coupled receptors. Nucleic. Acids Res., 2003, 31:294-297.
13. Fredriksson, R.; Lagerstrom, M.C.; Lundin, L.G.; Schioth, H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol., 2003, 63:1256-1272.
14. 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.
15. Wu, S.V.; Chen, M.C.; Rozengurt, E. Genomic organization, expression, and function of bitter taste receptors (T2R) in mouse and rat. Physiol, Genomics, 2005, 22:139-149.
16. Finger, T.E.; Bottger, B.; Hansen, A.; Anderson, K.T.; Alimohammadi, H.; Silver, W.L. Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration. Proc. Natl. Acad. Sci. U. S. A., 2003, 100:8981-8986.
17. 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.
18. Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS, Liggett SB: Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat. Med., 2010, 16:1299-1304.
19. 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.
20. Chen, X.; Gabitto, M.; Peng, Y.; Ryba, N.J.; Zuker, C.S. A gustotopic map of taste qualities in the mammalian brain. Science, 2011, 333:1262-1266.
21. Jeon, T.I.; Zhu, B.; Larson, J.L.; Osborne, T.F. SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice. J. Clin. Invest., 2008, 118:3693-3700.
22. Le Neve, B.; Foltz, M.; Daniel, H.; Gouka, R. 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., 2010.
23. Rozengurt, E.; Sternini, C. Taste receptor signaling in the mammalian gut. Curr. Opin. Pharmacol., 2007, 7:557-562.
24. Rozengurt, N.; Wu, S.V.; Chen, M.C.; Huang, C.; Sternini, C.; Rozengurt, E. Colocalization of the alpha-subunit of gustducin with PYY and GLP-1 in L cells of human colon. Am. J. Physiol. Gastrointest. Liver Physiol., 2006, 291:G792-802.
25. Dotson, C.D.; Zhang, L.; Xu, H.; Shin, Y.K.; Vigues, S.; Ott, S.H.; Elson, A.E.; Choi, H.J.; Shaw, H.; Egan J.M.; et al. Bitter taste receptors influence glucose homeostasis. PLoS One, 2008, 3:e3974.
26. Ritter, R.C.; Slusser, P.G.; Stone, S. Glucoreceptors controlling feeding and blood glucose: location in the hindbrain. Science, 1981, 213:451-452.
27. Oomura, Y.; Ono, T.; Ooyama, H.; Wayner, M.J. Glucose and osmosensitive neurones of the rat hypothalamus. Nature, 1969, 222:282-284.
28. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C.A.; Motoshima, H.; Fox, B.A.; Le Trong, I.; Teller, D.C.; Okada, T.; Stenkamp, R.E.; M. Yamamoto, M. Miyano. Crystal structure of rhodopsin: A G protein-coupled receptor. Science, 2000, 289:739-745.
29. Tate, C.G.; Grisshammer, R. Heterologous expression of Gprotein-coupled receptors. Trends Biotechnol,. 1996, 14:426-430.
30. Chelikani, P.; Reeves, P.J.; Rajbhandary, U.L.; Khorana, H.G. The synthesis and high-level expression of a beta2-adrenergic receptor gene in a tetracycline-inducible stable mammalian cell line. Protein Sci., 2006, 15:1433-1440.
31. Krautwurst, D.; Yau, K.W.; Reed, R.R. Identification of ligands for olfactory receptors by functional expression of a receptor library. Cell, 1998, 95:917-926.
32. Bufe, B.; Hofmann, T.; Krautwurst, D.; Raguse, J.D.; Meyerhof, W. The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides. Nat. Genet., 2002, 32:397-401.
33. Parola, A.L.; Kobilka, B.K. The peptide product of a 5' leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis. J. Biol. Chem., 1994, 269:4497-4505.
34. Subramaniam, K.; Chen, K.; Joseph, K.; Raymond, J.R.; Tholanikunnel, B.G. The 3'-untranslated region of the beta2-adrenergic receptor mRNA regulates receptor synthesis. J. Biol. Chem., 2004, 279:27108-27115.
35. Dey, S.; Matsunami, H. Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors. Proc. Natl. Acad. Sci. USA., 2011, 108:16651-16656.
36. Matsunami, H.; Mainland, J.D.; Dey, S. Trafficking of mammalian chemosensory receptors by receptor-transporting proteins. Ann. N. Y. Acad. Sci., 2009, 1170:153-156.
37. White, J.H.; Wise, A.; Main, M.J.; Green, A.; Fraser, N.J.; Disney, G.H.; Barnes, A.A.; Emson, P.; Foord, S.M.; Marshall, F.H. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature, 1998, 396:679-682.
38. McLatchie, L.M.; Fraser, N.J.; Main, M.J.; Wise, A.; Brown, J.; Thompson, N.; Solari, R.; Lee, M.G.; Foord, S.M. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature, 1998, 393:333-339.
39. Ilegems, E.; Iwatsuki, K.; Kokrashvili, Z.; Benard, O.; Ninomiya, Y.; Margolskee, R.F. REEP2 enhances sweet receptor function by recruitment to lipid rafts. J. Neurosci., 2010, 30:13774-13783.
40. Behrens, M.; Bartelt, J.; Reichling, C.; Winnig, M.; Kuhn, C.; Meyerhof, W. Members of RTP and REEP gene families influence functional bitter taste receptor expression. J. Biol. Chem., 2006, 281:20650-20659.
41. Pronin, A.N.; Tang, H.; Connor, J.; Keung, W. Identification of ligands for two human bitter T2R receptors. Chem. Senses, 2004, 29:583-593.
42. Singh, N.; Pydi, S.P.; Upadhyaya, J.; Chelikani, P. Structural Basis of Activation of Bitter Taste Receptor T2R1 and Comparison with Class A G-protein-coupled Receptors (GPCRs). J. Biol. Chem., 2011, 286:36032-36041.
43. Ueda, T.; Ugawa, S.; Yamamura, H.; Imaizumi, Y.; Shimada, S. Functional interaction between T2R taste receptors and G-protein alpha subunits expressed in taste receptor cells. J. Neurosci., 2003, 23:7376-7380.
44. Fox, A.L. The Relationship between Chemical Constitution and Taste. Proc. Natl. Acad. Sci. USA., 1932, 18:115-120.
45. Blakeslee, A.F. Genetics of Sensory Thresholds: Taste for Phenyl Thio Carbamide. Proc. Natl. Acad. Sci. USA., 1932, 18:120-130.
46. Kim, U.K.; Jorgenson, E.; Coon, H.; Leppert, M.; Risch, N.; Drayna, D. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide. Science, 2003, 299:1221-1225.
47. Campbell, M.C.; Ranciaro, A.; Froment, A.; Hirbo, J.; Omar, S.; Bodo, J.M.; Nyambo, T.; Lema, G.; Zinshteyn, D.; Drayna, D.; Breslin, P.A.; Tishkoff, S.A. Evolution of functionally diverse alleles associated with PTC bitter taste sensitivity in Africa. Mol. Biol. Evol., 2012, 29:1141-1153.
48. Wooding, S.; Kim, U.K.; Bamshad, M.J.; Larsen, J.; Jorde, L.B.; Drayna, D. Natural selection and molecular evolution in PTC, a bitter-taste receptor gene. Am. J. Hum. Genet., 2004, 74:637-646.
49. Floriano, W.B.; Hall, S.; Vaidehi, N.; Kim, U.; Drayna, D.; Goddard, W.A. 3rd. Modeling the human PTC bitter-taste receptor interactions with bitter tastants. J. Mol. Model., 2006, 12:931-941.
50. Miguet, L.; Zhang, Z.; Grigorov, M.G. Computational studies of ligand-receptor interactions in bitter taste receptors. J. Recept. Signal Transduct. Res., 2006, 26:611-630.
51. Tan, J.; Abrol, R.; Trzaskowski, B.; Goddard, W.A. The 3D structure prediction of TAS2R38 bitter receptors bound to agonists phenylthiocarbamide (PTC) and 6-n-Propylthiouracil (PROP). J. Chem. Inf. Model., 2012
52. Pronin, A.N.; Xu, H.; Tang, H.; Zhang, L.; Li, Q.; Li, X. Specific alleles of bitter receptor genes influence human sensitivity to the bitterness of aloin and saccharin. Curr. Biol., 2007, 17:1403-1408.
53. Kim, U.; Wooding, S.; Ricci, D.; Jorde, L.B.; Drayna, D. Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci. Hum. Mutat., 2005, 26:199-204.
54. Chakraborty, R.; Pydi, S.P.; Gleim, S.; Dakshinamurti, S.; Hwa, J.; Chelikani, P. Site-Directed Mutations and the Polymorphic Variant Ala160Thr in the Human Thromboxane Receptor Uncover a Structural Role for Transmembrane Helix 4. PLoS One, 2012, 7:e29996.
55. Ueda, T.; Ugawa, S.; Ishida, Y.; Shibata, Y.; Murakami, S.; Shimada, S. Identification of coding single-nucleotide polymorphisms in human taste receptor genes involving bitter tasting. Biochem. Biophys. Res. Commun., 2001, 285:147-151.
56. Brockhoff, A.; Behrens, M.; Niv, M.Y.; Meyerhof, W. Structural requirements of bitter taste receptor activation. Proc. Natl. Acad. Sci. USA., 2010, 107:11110-11115.
57. Sakurai, T.; Misaka, T.; Ishiguro, M.; Masuda, K.; Sugawara, T.; Ito, K.; Kobayashi, T.; Matsuo, S.; Ishimaru, Y.; Asakura, T.; Abe, K. Characterization of the beta-D-glucopyranoside binding site of the human bitter taste receptor hTAS2R16. J. Biol. Chem., 2010, 285:28373-28378.
58. Wang, W.; Dia, V.P.; Vasconez, M.; de Mejia, E.G.; Nelson, R.L. Analysis of soybean protein-derived peptides and the effect of cultivar, environmental conditions, and processing on lunasin concentration in soybean and soy products. J. A.O.A.C. Int., 2008, 91:936-946.
59. Wu, J.; Aluko, R.E. Quantitative structure-activity relationship study of bitter di-and tri-peptides including relationship with angiotensin I-converting enzyme inhibitory activity. J. Pept. Sci., 2007, 13:63-69.
60. Ishibashi, N. O.I.; Kato, K.; Shigenaga, T.; Shinoda, I.; Okai, H.; Fukui, S. Role of the Hydrophobic Amino Acid Residue in the Bitterness of Peptides. Agric. Biol. Chem., 1988, 52:91-94.
61. Maehashi, K.; Matano, M.; Wang, H.; Vo, L.A.; Yamamoto, Y.; Huang, L. Bitter peptides activate hTAS2Rs, the human bitter receptors. Biochem. Biophys. Res. Commun., 2008, 365:851-855.
62. Upadhyaya, J.; Pydi, S.P.; Singh, N.; Aluko, R.E.; Chelikani, P. Bitter taste receptor T2R1 is activated by dipeptides and tripeptides. Biochem. Biophys. Res. Commun., 2010, 398:331-335.
63. Smith, S.O. Structure and activation of the visual pigment rhodopsin. Ann. Rev. Biophys., 2010, 39:309-328.
64. Arakawa, M.; Chakraborty, R.; Upadhyaya, J.; Eilers, M.; Reeves, P.J.; Smith, S.O.; Chelikani, P. Structural and functional role of small group-conserved amino acids present on helix-H7 in the beta(2)-adrenergic receptor. Biochim. Biophys. Acta, 2011, 1808:1170-1178.
65. Arakawa, M.; Yanamala, N.; Upadhyaya, J.; Halayko, A.; Klein-Seetharaman, J.; Chelikani, P. The importance of valine 114 in ligand binding in beta(2)-adrenergic receptor. Protein Sci., 2010, 19:85-93.
66. Fritze, O.; Filipek, S.; Kuksa, V.; Palczewski, K.; Hofmann, K.P.; Ernst, O.P. Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activation. Proc. Natl. Acad. Sci. USA., 2003, 100:2290-2295.
67. Ramon, E.; del Valle, L.J.; Garriga, P. Unusual thermal and conformational properties of the rhodopsin congenital night blindness mutant Thr-94 --> Ile. J. Biol. Chem., 2003, 278:6427-6432.
68. Pydi, S.P.; Bhullar, R.P.; Chelikani, P. Constitutively active mutant gives novel insights into the mechanism of bitter taste receptor activation. J. Neurochem., 2012, 122:537-544.
69. Rasmussen, S.G.; Choi, H.J.; Fung, J.J.; Pardon, E.; Casarosa, P.; Chae, P.S.; Devree, B.T.; Rosenbaum, D.M.; Thian, F.S.; Kobilka, T.S.; Schnapp, A.; Konetzki, I.; Sunahara, R.K.; Gellman, S.H.; Pautsch, A.; Steyaert, J.; Weis, W.I.; Kobilka, B.K. Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor. Nature, 2011, 469:175-180.
70. Standfuss, J.; Edwards, P.C.; D'Antona, A.; Fransen, M.; Xie, G.; Oprian, D.D.; Schertler, G.F. The structural basis of agonistinduced activation in constitutively active rhodopsin. Nature, 2011, 471:656-660.
71. Angel, TE.; Chance, M.R.; Palczewski, K. Conserved waters mediate structural and functional activation of family A (rhodopsinlike) G protein-coupled receptors. Proc. Natl. Acad. Sci. USA., 2009, 106:8555-8560.
72. Nygaard, R.; Valentin-Hansen, L.; Mokrosinski, J.; Frimurer, T.M.; Schwartz, T.W. Conserved water-mediated hydrogen bond network between TM-I, -II, -VI, and -VII in 7TM receptor activation. J. Biol. Chem., 2010, 285:19625-19636.
73. Ross, E.M.; Wilkie, T.M. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu. Rev. Biochem., 2000, 69:795-827.
74. Oldham, W.M.; Hamm, H.E. Heterotrimeric G protein activation by G-protein-coupled receptors. Nat. Rev. Mol. Cell Biol., 2008, 9:60-71.
75. Kozasa, T.; Hajicek, N.; Chow, C.R.; Suzuki, N. Signalling mechanisms of RhoGTPase regulation by the heterotrimeric G proteins G12 and G13. J. Biochem., 2011, 150:357-369.
76. Aittaleb, M.; Boguth, C.A.; Tesmer, J.J. Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors. Mol. Pharmacol., 2010, 77:111-125.
77. McLaughlin, S.K.; McKinnon, P.J.; Margolskee, R.F. Gustducin is a taste-cell-specific G protein closely related to the transducins. Nature, 1992, 357:563-569.
78. Hevezi, P.; Moyer, B.D.; Lu, M.; Gao, N.; White, E.; Echeverri, F.; Kalabat, D.; Soto, H.; Laita, B.; Li, C.; Yeh, S.A.; Zoller, M.; Zlotnik, A. Genome-wide analysis of gene expression in primate taste buds reveals links to diverse processes. PLoS One, 2009, 4:e6395.
79. Rasmussen, S.G.; Devree, B.T.; Zou, Y.; Kruse, A.C.; Chung, K.Y.; Kobilka, T.S.; Thian, F.S.; Chae, P.S.; Pardon, E.; Calinski, D.; Mathiesen, J.M.; Shah, S.T.; Lyons, J.A.; Caffrey, M.; Gellman, S.H.; Steyaert, J.; Skiniotis, G.; Weis, W.I.; Sunahara, R.K.; Kobilka, B.K. Crystal structure of the beta(2) adrenergic receptor-Gs protein complex. Nature, 2011, 477:549-555.