TAS2R14 explained

Taste receptor type 2 member 14 is a protein that in humans is encoded by the TAS2R14 gene.^{[1] [2] [3]}

Taste receptors for bitter substances (T2Rs/TAS2Rs) belong to the family of G-protein coupled receptors and are related to class A-like GPCRs. There are 25 known T2Rs in humans responsible for bitter taste perception.^[4]

Bitter taste receptor hTAS2R14 is one of the human bitter taste receptors, recognizing an enormous variety of structurally different molecules, including natural and synthetic bitter compounds.^[5]

Gene

TAS2R14 gene (Taste receptor type 2 member 14) is a Protein Coding gene. This gene maps to the taste receptor gene cluster on chromosome 12p13.^[6]

An important paralog of this gene is TAS2R13.

SNPs

Taste receptors harbor many polymorphisms, and several SNPs have a profound impact on the gene function and expression.

Common TAS2R14 SNPs location!Mutation!dbSNP

I5M	rs79297986
F63L	rs142263768
C67S	rs140545738
T86A	rs16925868
N87Y	rs146833217
I118V	rs4140968
F198L	rs202123922
L201F	rs35804287
K211R	rs111614880

Data obtained from 1000 genomes project.

Site-directed mutagenesis

The following residues have been subjected to site-directed mutagenesis.^[7]

Location	BW number^[8]	Residue
TM2	2.61	W66
ECL1	3.28	L85
ECL1	3.29	T86
ECL1	3.3	N87
TM3	3.32	W89
TM3	3.33	T90
TM3	3.36	N93
TM3	3.37	H94
ECL2	5.42	T182
ECL2	5.43	S183
TM5	5.46	F186
TM5	5.47	I187
TM6	6.48	Y240
TM6	6.49	A241
TM6	6.51	F243
TM6	6.55	F247
TM7	7.36	I263
TM7	7.39	Q266
TM7	7.42	G269

Signal transduction pathways

TAS2Rs activation produces modulation of a broad range of signal transduction pathways. The Gαgusducin (Gαgus), which belongs to the Gαi subfamily, was first identified and cloned in 1992 intaste tissue, and has high similarity to the Gα-transducin (Gαtrans) in the retina.Gα16gus44, a chimeric Gα16 (type of Gαq), harboring 44 gustducin specific sequence at its C terminus, or Gαqi5, a Gαq protein containing the five carboxyl-terminal amino acids from Gαi, are often used in order to couple the taste receptor to Gαq pathway and measure calcium or IP3 release.Specifically, stimulation of a GPCR receptor, coupled to Gαq, results in the activation of phospholipase C β2 (PLC), which then stimulates the second messengers 1,4,5-inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 causes the release of Ca+2 from intracellular stores. Calcium opens Ca-activated TRP ion channels and leads to depolarization of the cell as well as to release of neurotransmitters.^[9]

Ligands

To date, 151 ligands have been identified for T2R14,^{[10] [11]} in addition to 12 synthetic flufenamic acid derivatives.^[12]  

Tissue distribution

In addition to the tongue, TAS2R14 is expressed in many other tissues including the heart,^[13] thyroid,^[14] stomach,^[15] skin,^[16] urogenital,^{[17] [18] [19] [20]} immune system,^[21] and more.

Function

This gene product belongs to the family of taste receptors that are members of the G-protein-coupled receptor superfamily. These proteins are specifically expressed in the taste receptor cells of the tongue and palate epithelia. They are organized in the genome in clusters and are genetically linked to loci that influence bitter perception in mice and humans. In functional expression studies, TAS2R14 responds to (−)-α-thujone, the primary neurotoxic agent in absinthe, and picrotoxin, a poison found in fishberries.^[22] This gene maps to the taste receptor gene cluster on chromosome 12p13.

TAS2R14 is also expressed in the smooth muscle of human airways, along with several other bitter taste receptors. Their activation in these cells causes an increase in intracellular calcium ion, which in turn triggers the opening of potassium channels which hyperpolarize the membrane and cause the smooth muscle to relax. Hence, activation of these receptors leads to bronchodilation.^[23]

In the respiratory system, several TAS2R subtypes: TAS2R4, TAS2R16, TAS2R14 and TAS2R38, were found to play important roles in innate immune nitric oxide production (NO).^[24]

T2R14 causes inhibition of IgE-dependent mast cells.^[25]

Associations between single nucleotide polymorphisms in TAS214 gene and male infertility were observed.

See also

• Taste receptor

Further reading

• Kinnamon SC . A plethora of taste receptors . Neuron . 25 . 3 . 507–510 . March 2000 . 10774719 . 10.1016/S0896-6273(00)81054-5 . free .
• Margolskee RF . Molecular mechanisms of bitter and sweet taste transduction . The Journal of Biological Chemistry . 277 . 1 . 1–4 . January 2002 . 11696554 . 10.1074/jbc.R100054200 . free .
• Montmayeur JP, Matsunami H . Receptors for bitter and sweet taste . Current Opinion in Neurobiology . 12 . 4 . 366–371 . August 2002 . 12139982 . 10.1016/S0959-4388(02)00345-8 . 37807140 .
• Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ . 6 . T2Rs function as bitter taste receptors . Cell . 100 . 6 . 703–711 . March 2000 . 10761935 . 10.1016/S0092-8674(00)80706-0 . 7293493 . free .
• Zhang Y, Hoon MA, Chandrashekar J, Mueller KL, Cook B, Wu D, Zuker CS, Ryba NJ . 6 . Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways . Cell . 112 . 3 . 293–301 . February 2003 . 12581520 . 10.1016/S0092-8674(03)00071-0 . 718601 . free .
• Fischer A, Gilad Y, Man O, Pääbo S . Evolution of bitter taste receptors in humans and apes . Molecular Biology and Evolution . 22 . 3 . 432–436 . March 2005 . 15496549 . 10.1093/molbev/msi027 . free .
• Go Y, Satta Y, Takenaka O, Takahata N . Lineage-specific loss of function of bitter taste receptor genes in humans and nonhuman primates . Genetics . 170 . 1 . 313–326 . May 2005 . 15744053 . 1449719 . 10.1534/genetics.104.037523 .
• Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore RJ, Smith RD . Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry . Journal of Proteome Research . 4 . 6 . 2070–2080 . 2006 . 16335952 . 1850943 . 10.1021/pr0502065 .
• 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 . The Journal of Biological Chemistry . 281 . 29 . 20650–20659 . July 2006 . 16720576 . 10.1074/jbc.M513637200 . free .

Notes and References

1. Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS . A novel family of mammalian taste receptors . Cell . 100 . 6 . 693–702 . March 2000 . 10761934 . 10.1016/S0092-8674(00)80705-9 . 14604586 . free .
2. Matsunami H, Montmayeur JP, Buck LB . A family of candidate taste receptors in human and mouse . Nature . 404 . 6778 . 601–604 . April 2000 . 10766242 . 10.1038/35007072 . 2000Natur.404..601M . 4336913 .
3. Web site: Entrez Gene: TAS2R14 taste receptor, type 2, member 14.
4. Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M . 6 . The molecular receptive ranges of human TAS2R bitter taste receptors . Chemical Senses . 35 . 2 . 157–170 . February 2010 . 20022913 . 10.1093/chemse/bjp092 . free .
5. Di Pizio A, Niv MY . Promiscuity and selectivity of bitter molecules and their receptors . Bioorganic & Medicinal Chemistry . 23 . 14 . 4082–4091 . July 2015 . 25934224 . 10.1016/j.bmc.2015.04.025 .
6. Web site: TAS2R14 Gene - GeneCards | T2R14 Protein | T2R14 Antibody . 2021-08-03. www.genecards.org.
7. Nowak S, Di Pizio A, Levit A, Niv MY, Meyerhof W, Behrens M . Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14 . Biochimica et Biophysica Acta (BBA) - General Subjects . 1862 . 10 . 2162–2173 . October 2018 . 30009876 . 10.1016/j.bbagen.2018.07.009. 51628536 .
8. 1995-01-01. [19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors]. Methods in Neurosciences. en. 25. 366–428. 10.1016/S1043-9471(05)80049-7. 1043-9471. Ballesteros. Juan A.. Weinstein. Harel. 9780121852955.
9. Breer H, Boekhoff I, Tareilus E . Rapid kinetics of second messenger formation in olfactory transduction . Nature . 345 . 6270 . 65–68 . May 1990 . 2158631 . 10.1038/345065a0 . 511452 . 1990Natur.345...65B .
10. Wiener A, Shudler M, Levit A, Niv MY . BitterDB: a database of bitter compounds . Nucleic Acids Research . 40 . Database issue . D413–D419 . January 2012 . 21940398 . 3245057 . 10.1093/nar/gkr755 .
11. Dagan-Wiener A, Di Pizio A, Nissim I, Bahia MS, Dubovski N, Margulis E, Niv MY . BitterDB: taste ligands and receptors database in 2019 . Nucleic Acids Research . 47 . D1 . D1179–D1185 . January 2019 . 30357384 . 6323989 . 10.1093/nar/gky974 .
12. Di Pizio A, Waterloo LA, Brox R, Löber S, Weikert D, Behrens M, Gmeiner P, Niv MY . 6 . Rational design of agonists for bitter taste receptor TAS2R14: from modeling to bench and back . Cellular and Molecular Life Sciences . 77 . 3 . 531–542 . February 2020 . 31236627 . 10.1007/s00018-019-03194-2 . 195329795 . 11104859 .
13. Foster SR, Porrello ER, Purdue B, Chan HW, Voigt A, Frenzel S, Hannan RD, Moritz KM, Simmons DG, Molenaar P, Roura E, Boehm U, Meyerhof W, Thomas WG . 6 . Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart . PLOS ONE . 8 . 5 . e64579 . 2013 . 23696900 . 3655793 . 10.1371/journal.pone.0064579 . free . 2013PLoSO...864579F .
14. Clark AA, Dotson CD, Elson AE, Voigt A, Boehm U, Meyerhof W, Steinle NI, Munger SD . 6 . TAS2R bitter taste receptors regulate thyroid function . FASEB Journal . 29 . 1 . 164–172 . January 2015 . 25342133 . 4285546 . 10.1096/fj.14-262246 . free .
15. Liszt KI, Ley JP, Lieder B, Behrens M, Stöger V, Reiner A, Hochkogler CM, Köck E, Marchiori A, Hans J, Widder S, Krammer G, Sanger GJ, Somoza MM, Meyerhof W, Somoza V . 6 . Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells . Proceedings of the National Academy of Sciences of the United States of America . 114 . 30 . E6260–E6269 . July 2017 . 28696284 . 5544304 . 10.1073/pnas.1703728114 . free . 2017PNAS..114E6260L .
16. Shaw L, Mansfield C, Colquitt L, Lin C, Ferreira J, Emmetsberger J, Reed DR . Personalized expression of bitter 'taste' receptors in human skin . PLOS ONE . 13 . 10 . e0205322 . 2018 . 30332676 . 6192714 . 10.1371/journal.pone.0205322 . free . 2018PLoSO..1305322S .
17. 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 . The Journal of Biological Chemistry . 281 . 29 . 20650–20659 . July 2006 . 16720576 . 10.1074/jbc.M513637200 . free .
18. Zheng K, Lu P, Delpapa E, Bellve K, Deng R, Condon JC, Fogarty K, Lifshitz LM, Simas TA, Shi F, ZhuGe R . 6 . Bitter taste receptors as targets for tocolytics in preterm labor therapy . FASEB Journal . 31 . 9 . 4037–4052 . September 2017 . 28559440 . 5572693 . 10.1096/fj.201601323RR . free .
19. Gentiluomo M, Crifasi L, Luddi A, Locci D, Barale R, Piomboni P, Campa D . Taste receptor polymorphisms and male infertility . Human Reproduction . 32 . 11 . 2324–2331 . November 2017 . 29040583 . 10.1093/humrep/dex305 . free .
20. Martin LT, Nachtigal MW, Selman T, Nguyen E, Salsman J, Dellaire G, Dupré DJ . Bitter taste receptors are expressed in human epithelial ovarian and prostate cancers cells and noscapine stimulation impacts cell survival . Molecular and Cellular Biochemistry . 454 . 1–2 . 203–214 . April 2019 . 30350307 . 10.1007/s11010-018-3464-z . 53035462 .
21. Orsmark-Pietras C, James A, Konradsen JR, Nordlund B, Söderhäll C, Pulkkinen V, Pedroletti C, Daham K, Kupczyk M, Dahlén B, Kere J, Dahlén SE, Hedlin G, Melén E . 6 . Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics . The European Respiratory Journal . 42 . 1 . 65–78 . July 2013 . 23222870 . 10.1183/09031936.00077712 . free .
22. Behrens M, Brockhoff A, Kuhn C, Bufe B, Winnig M, Meyerhof W . The human taste receptor hTAS2R14 responds to a variety of different bitter compounds . Biochemical and Biophysical Research Communications . 319 . 2 . 479–485 . June 2004 . 15178431 . 10.1016/j.bbrc.2004.05.019 .
23. Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS, Liggett SB . 6 . Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction . Nature Medicine . 16 . 11 . 1299–1304 . November 2010 . 20972434 . 3066567 . 10.1038/nm.2237 .
24. Yan CH, Hahn S, McMahon D, Bonislawski D, Kennedy DW, Adappa ND, Palmer JN, Jiang P, Lee RJ, Cohen NA . 6 . Nitric oxide production is stimulated by bitter taste receptors ubiquitously expressed in the sinonasal cavity . American Journal of Rhinology & Allergy . 31 . 2 . 85–92 . March 2017 . 28452704 . 5356199 . 10.2500/ajra.2017.31.4424 .
25. Ekoff M, Choi JH, James A, Dahlén B, Nilsson G, Dahlén SE . Bitter taste receptor (TAS2R) agonists inhibit IgE-dependent mast cell activation . The Journal of Allergy and Clinical Immunology . 134 . 2 . 475–478 . August 2014 . 24755408 . 10.1016/j.jaci.2014.02.029 .