A functional comparison of the domestic cat bitter receptors Tas2r38 and Tas2r43 with their human orthologs

BMC Neuroscience

Nancy E Rawson²  Joseph B Rucker¹  Anu Thomas¹  Jason R Goodman¹  Michelle M Sandau² 

[1] Integral Molecular, Inc., Philadelphia, PA, USA;AFB International, St. Charles, MO, USA

关键词: Tas2r43;    Tas2r38;    taste;    domestic cat;    feline;    flavor;    Bitter;   

Others  :  1211790
DOI  :  10.1186/s12868-015-0170-6

 received in 2014-09-11, accepted in 2015-05-07,  发布年份 2015

【 摘 要 】

Background

Domestic cats (felis catus) have a reputation for being rather unpredictable in their dietary choices. While their appetite for protein or savory flavors is consistent with their nutritional needs, their preference among protein-sufficient dietary options may relate to differences in the response to other flavor characteristics. Studies of domestic cat taste perception are limited, in part, due to the lack of receptor sequence information. Several studies have described the phylogenetic relationship of specific cat taste receptor sequences as compared with other carnivores. For example, domestic cats are obligate carnivores and their receptor Tas1r2, associated with the human perception of sweet, is present only as a pseudogene. Similarly, the cat perception of bitter may differ from that of other mammals due to variations in their repertoire of bitter receptor (Tas2r) genes. This report includes the first functional characterization of domestic cat taste receptors.

Results

We functionally expressed two uncharacterized domestic sequences Tas2r38 and Tas2r43 and deorphanized the receptors using a cellular functional assay. Statistical significance was determined using an unpaired, two-tailed t-test. The cat sequence for Tas2r38 contains 3 major amino acid residues known to confer the taster phenotype (PAI), which is associated with sensitivity to the bitter compounds PROP and PTC. However, in contrast to human TAS2R38, cat Tas2r38 is activated by PTC but not by PROP. Furthermore, like its human counterpart, cat Tas2r43 is activated by aloin and denatonium, but differs from the human TAS2R43 by insensitivity to saccharin. The responses of both cat receptors to the bitter ligands were concentration-dependent and were inhibited by the human bitter blocker probenecid.

Conclusions

These data demonstrate that the response profiles of the cat bitter receptors Tas2r38 and Tas2r43 are distinct from those of their orthologous human receptors. Results with cat Tas2r38 also demonstrate that additional residues beyond those classically associated with PROP sensitivity in humans influence the sensitivity to PROP and PTC. Functional studies of the human bitter receptor family are being applied to the development of food and medicinal products with more appealing flavor profiles. Our work lays the foundation for similar work applied to felines.

【 授权许可】

   
2015 Sandau et al.; licensee BioMed Central.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Breslin PA: An evolutionary perspective on food and human taste. Curr Biol 2013, 23:R409-R418.
• [2]Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS: A novel family of mammalian taste receptors. Cell 2000, 100:693-702.
• [3]Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ: T2Rs function as bitter taste receptors. Cell 2000, 100:703-711.
• [4]Matsunami H, Montmayeur JP, Buck LB: A family of candidate taste receptors in human and mouse. Nature 2000, 404:601-604.
• [5]Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M: The molecular receptive ranges of human TAS2R bitter taste receptors. Chem Senses 2010, 35:157-170.
• [6]Wiener A, Shudler M, Levit A, Niv MY: BitterDB: a database of bitter compounds. Nucleic Acids Res 2012, 40:D413-D419.
• [7]Conte C, Ebeling M, Marcuz A, Nef P, Andres-Barquin PJ: Identification and characterization of human taste receptor genes belonging to the TAS2R family. Cytogenet Genome Res 2002, 98:45-53.
• [8]Kim U, Wooding S, Ricci D, Jorde LB, Drayna D: Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci. Hum Mutat 2005, 26:199-204.
• [9]Drewnowski A, Gomez-Carneros C: Bitter taste, phytonutrients, and the consumer: a review. Am J Clin Nutr 2000, 72:1424-1435.
• [10]Hofmann T: Taste-active maillard reaction products: the "tasty" world of nonvolatile maillard reaction products. Ann N Y Acad Sci 2005, 1043:20-29.
• [11]Maehashi K, Matano M, Wang H, Vo LA, Yamamoto Y, Huang L: Bitter peptides activate hTAS2Rs, the human bitter receptors. Biochem Biophys Res Commun 2008, 365:851-855.
• [12]Greene TA, Alarcon S, Thomas A, Berdougo E, Doranz BJ, Breslin PA, Rucker JB: Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One 2011., 6Article ID e20123
• [13]Brockhoff A, Behrens M, Roudnitzky N, Appendino G, Avonto C, Meyerhof W: Receptor agonism and antagonism of dietary bitter compounds. J Neurosci 2011, 31:14775-14782.
• [14]Slack JP, Brockhoff A, Batram C, Menzel S, Sonnabend C, Born S, Galindo MM, Kohl S, Thalmann S, Ostopovici-Halip L, et al.: Modulation of bitter taste perception by a small molecule hTAS2R antagonist. Curr Biol 2010, 20:1104-1109.
• [15]Kinnamon SC, Margolskee RF: Mechanisms of taste transduction. Curr Opin Neurobiol 1996, 6:506-513.
• [16]Margolskee RF: Molecular mechanisms of bitter and sweet taste transduction. J Biol Chem 2002, 277:1-4.
• [17]Brockhoff A, Behrens M, Niv MY, Meyerhof W: Structural requirements of bitter taste receptor activation. Proc Natl Acad Sci U S A 2010, 107:11110-11115.
• [18]Born S, Levit A, Niv MY, Meyerhof W, Behrens M: The human bitter taste receptor TAS2R10 is tailored to accommodate numerous diverse ligands. J Neurosci 2013, 33:201-213.
• [19]Bufe B, Breslin PA, Kuhn C, Reed DR, Tharp CD, Slack JP, Kim UK, Drayna D, Meyerhof W: The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception. Curr Biol 2005, 15:322-327.
• [20]Pronin AN, 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.
• [21]Li D, Zhang J: Diet shapes the evolution of the vertebrate bitter taste receptor gene repertoire. Mol Biol Evol 2014, 31:303-309.
• [22]Bachmanov AA, Beauchamp GK: Taste receptor genes. Annu Rev Nutr 2007, 27:389-414.
• [23]Boughter JD, Jr., Bachmanov AA: Behavioral genetics and taste. BMC Neurosci 2007, 8 Suppl 3:S3.
• [24]Li X, Li W, Wang H, Cao J, Maehashi K, Huang L, Bachmanov AA, Reed DR, Legrand-Defretin V, Beauchamp GK, Brand JG: Pseudogenization of a sweet-receptor gene accounts for cats' indifference toward sugar. PLoS Genet 2005, 1:27-35.
• [25]Jiang P, Josue J, Li X, Glaser D, Li W, Brand JG, Margolskee RF, Reed DR, Beauchamp GK: Major taste loss in carnivorous mammals. Proc Natl Acad Sci U S A 2012, 109:4956-4961.
• [26]Boudreau JC, Bradley BE, Bierer PR, Kruger S, Tsuchitani C: Single unit recordings from the geniculate ganglion of the facial nerve of the cat. Experimental brain research Experimentelle Hirnforschung Experimentation cerebrale 1971, 13:461-488.
• [27]Boudreau JCaW, T.D: Flavor Chemistry of Carnivore Taste Systems ACS Symposium Series. Flavor Chemistry of Carnivore Taste Systems 1978, 102-128.
• [28]Carpenter JA: Species differences in taste preferences. J Comp Physiol Psychol 1956, 49:139-144.
• [29]Mojet J, Christ-Hazelhof E, Heidema J: Taste perception with age: generic or specific losses in threshold sensitivity to the five basic tastes? Chem Senses 2001, 26:845-860.
• [30]McMahon DB, Shikata H, Breslin PA: Are human taste thresholds similar on the right and left sides of the tongue? Chem Senses 2001, 26:875-883.
• [31]Rofe PC, Anderson RS: Food preference in domestic pets. Proc Nutr Soc 1970, 29:330-335.
• [32]Biró Z, Lanszki J, Szemethy L, Heltai M, Randi E: Feeding habits of feral domestic cats (Felis catus), wild cats (Felis silvestris) and their hybrids: trophic niche overlap among cat groups in Hungary. J Zool 2005, 266:187-196.
• [33]Plantinga EA, Bosch G, Hendriks WH: Estimation of the dietary nutrient profile of free-roaming feral cats: possible implications for nutrition of domestic cats. Br J Nutr 2011, 106(Suppl 1):S35-S48.
• [34]Lee RJ, Cohen NA: Bitter and sweet taste receptors in the respiratory epithelium in health and disease. J Mol Med (Berl) 2014, 92:1235-1244.
• [35]Lee RJ, Xiong G, Kofonow JM, Chen B, Lysenko A, Jiang P, Abraham V, Doghramji L, Adappa ND, Palmer JN, et al.: T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J Clin Invest 2012, 122:4145-4159.
• [36]Tizzano M, Gulbransen BD, Vandenbeuch A, Clapp TR, Herman JP, Sibhatu HM, Churchill ME, Silver WL, Kinnamon SC, Finger TE: Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci U S A 2010, 107:3210-3215.
• [37]Oike H, Nagai T, Furuyama A, Okada S, Aihara Y, Ishimaru Y, Marui T, Matsumoto I, Misaka T, Abe K: Characterization of ligands for fish taste receptors. J Neurosci 2007, 27:5584-5592.
• [38]Bufe B, Hofmann T, Krautwurst D, Raguse JD, Meyerhof W: The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides. Nat Genet 2002, 32:397-401.
• [39]Wooding S, Bufe B, Grassi C, Howard MT, Stone AC, Vazquez M, Dunn DM, Meyerhof W, Weiss RB, Bamshad MJ: Independent evolution of bitter-taste sensitivity in humans and chimpanzees. Nature 2006, 440:930-934.
• [40]Imai H, Suzuki N, Ishimaru Y, Sakurai T, Yin L, Pan W, Abe K, Misaka T, Hirai H: Functional diversity of bitter taste receptor TAS2R16 in primates. Biol Lett 2012.
• [41]Pronin AN, Tang H, Connor J, Keung W: Identification of ligands for two human bitter T2R receptors. Chem Senses 2004, 29:583-593.
• [42]Behrens M, Korsching SI, Meyerhof W: Tuning Properties of Avian and Frog Bitter Taste Receptors Dynamically Fit Gene Repertoire sizes. Mol Biol Evol 2014.
• [43]Sainz E, Cavenagh MM, Gutierrez J, Battey JF, Northup JK, Sullivan SL: Functional characterization of human bitter taste receptors. Biochem J 2007, 403:537-543.
• [44]Kuhn C, Bufe B, Winnig M, Hofmann T, Frank O, Behrens M, Lewtschenko T, Slack JP, Ward CD, Meyerhof W: Bitter taste receptors for saccharin and acesulfame K. J Neurosci 2004, 24:10260-10265.
• [45]Soranzo N, Bufe B, Sabeti PC, Wilson JF, Weale ME, Marguerie R, Meyerhof W, Goldstein DB: Positive selection on a high-sensitivity allele of the human bitter-taste receptor TAS2R16. Curr Biol 2005, 15:1257-1265.
• [46]Mullikin JC, Hansen NF, Shen L, Ebling H, Donahue WF, Tao W, Saranga DJ, Brand A, Rubenfield MJ, Young AC, et al.: Light whole genome sequence for SNP discovery across domestic cat breeds. BMC Genomics 2010, 11:406. BioMed Central Full Text
• [47]Pontius JU, Mullikin JC, Smith DR, Lindblad-Toh K, Gnerre S, Clamp M, Chang J, Stephens R, Neelam B, Volfovsky N, et al.: Initial sequence and comparative analysis of the cat genome. Genome Res 2007, 17:1675-1689.
• [48]Hu LL, Shi P: Smallest bitter taste receptor (T2Rs) gene repertoire in carnivores. Dongwuxue Yanjiu 2013, 34:E75-E81.
• [49]Zhou Y, Dong D, Zhang S, Zhao H: Positive selection drives the evolution of bat bitter taste receptor genes. Biochem Genet 2009, 47:207-215.
• [50]Go Y, Satta Y, Takenaka O, Takahata N: Lineage-specific loss of function of bitter taste receptor genes in humans and nonhuman primates. Genetics 2005, 170:313-326.
• [51]Dong D, Jones G, Zhang S: Dynamic evolution of bitter taste receptor genes in vertebrates. BMC Evol Biol 2009, 9:12. BioMed Central Full Text
• [52]Kim UK, 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.
• [53]Shi P, Zhang J, Yang H, Zhang YP: Adaptive diversification of bitter taste receptor genes in Mammalian evolution. Mol Biol Evol 2003, 20:805-814.
• [54]Roudnitzky N, Bufe B, Thalmann S, Kuhn C, Gunn HC, Xing C, Crider BP, Behrens M, Meyerhof W, Wooding SP: Genomic, genetic and functional dissection of bitter taste responses to artificial sweeteners. Hum Mol Genet 2011, 20:3437-3449.
• [55]Montague MJ, Li G, Gandolfi B, Khan R, Aken BL, Searle SM, Minx P, Hillier LW, Koboldt DC, Davis BW, et al.: Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication. Proc Natl Acad Sci U S A 2014, 111:17230-17235.
• [56]Biarnes X, Marchiori A, Giorgetti A, Lanzara C, Gasparini P, Carloni P, Born S, Brockhoff A, Behrens M, Meyerhof W: Insights into the binding of Phenyltiocarbamide (PTC) agonist to its target human TAS2R38 bitter receptor. PLoS One 2010., 5Article ID e12394
• [57]Tan J, Abrol R, Trzaskowski B, Goddard WA 3rd: 3D structure prediction of TAS2R38 bitter receptors bound to agonists phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). J Chem Inf Model 2012, 52:1875-1885.
• [58]Marchiori A, Capece L, Giorgetti A, Gasparini P, Behrens M, Carloni P, Meyerhof W: Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding. PLoS One 2013., 8Article ID e64675
• [59]Wyrwicka W, Clemente CD: Acceptance of high concentration saccharin solutions by cats after hypothalamic lesions. Exp Neurol 1973, 40:367-376.
• [60]Li H, Pakstis AJ, Kidd JR, Kidd KK: Selection on the human bitter taste gene, TAS2R16, in Eurasian populations. Hum Biol 2011, 83:363-377.
• [61]Behrens M, Meyerhof W: Oral and extraoral bitter taste receptors. Results Probl Cell Differ 2010, 52:87-99.
• [62]Behrens M, Meyerhof W: Gustatory and extragustatory functions of mammalian taste receptors. Physiol Behav 2011, 105:4-13.