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Published in:

28-09-2024 | REVIEW

Activation Dynamics for the Taste Receptor as an Energy Sensor

Authors: Keisuke Sanematsu, Noriatsu Shigemura

Published in: Current Oral Health Reports | Issue 4/2024

Abstract

Purpose of Review

Sweet-taste receptors play a crucial role in maintaining biological homeostasis by acting as energy sensors. However, the dynamics of this receptor after binding remain unknown because previous studies have primarily examined the static binding of the sweet taste receptor in complex with ligands. This review focuses on the mechanisms underlying the allostery-mediated activation and inactivation of the transmembrane domain of the sweet taste receptor subunit, TAS1R3.

Recent Findings

Molecular dynamics simulations predicted that agonist binding induces the opening of the ionic lock formed by transmembrane helices III and VI. These simulations were validated by functional assays in HEK293 cells expressing the sweet taste receptor.

Summary

The allostery through the interaction between the transmembrane domain of TAS1R3 and agonist would induce the conformational change on the intracellular side of the receptor, facilitating binding with the Gα subunit.

Lindemann B. Taste reception. Physiol Rev. 1996/07/01. 1996;76:719–66. https://doi.org/10.1152/physrev.1996.76.3.719

Montmayeur JP, Matsunami H. Receptors for bitter and sweet taste. Curr Opin Neurobiol. 2002/07/26. 2002;12:366–71. https://doi.org/10.1016/s0959-4388(02)00345-8

Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell 2001/08/18. 2001;106:381–90.https://doi.org/10.1016/s0092-8674(01)00451-2CrossRef

Greg Nelson J, Chandrashekar MA, Hoon L, Feng G, Zhao, Nicholas JP, Ryba, et al. An amino-acid taste receptor. Nature. 2002;416:199–202.CrossRefPubMed

Wong GT, Gannon KS, Margolskee RF. Transduction of bitter and sweet taste by gustducin. Nature. 1996/6/27. 1996;381:796–800. https://doi.org/10.1038/381796a0

Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W et al. T2Rs function as bitter taste receptors. Cell. 2000/04/13. 2000;100:703–11. https://doi.org/10.1016/s0092-8674(00)80706-0 [pii]

Chandrashekar J, Hoon MA, Ryba NJP, Zuker CS. The receptors and cells for mammalian taste. Nature. 2006/11/17 2006;444:288–94. https://doi.org/10.1038/nature05401.

Li X, Staszewski L, Xu H, Durick K, Zoller M, Adler E. Human receptors for sweet and umami taste. Proc Natl Acad Sci U S A. 2002/03/28. 2002;99:4692–6. https://doi.org/10.1073/pnas.072090199072090199 [pii].

Oka Y, Butnaru M, von Buchholtz L, Ryba NJ, Zuker CS. High salt recruits aversive taste pathways. Nature. 2013/02/15. 2013;494:472–5. nature11905 [pii]. https://doi.org/10.1038/nature11905

10.

Avenet P, Lindemann B. Amiloride-blockable sodium currents in isolated taste receptor cells. J Membr Biol. 1988/11/01. 1988;105:245–55. https://doi.org/10.1007/BF01871001.

11.

Murata Y, Yasuo T, Yoshida R, Obata K, Yanagawa Y, Margolskee RF et al. Action potential-enhanced ATP release from taste cells through hemichannels. J Neurophysiol. 2010/06/04. 2010;104:896–901. jn.00414.2010 [pii] https://doi.org/10.1152/jn.00414.2010

12.

Heck GL, Mierson S, DeSimone JA. Salt taste transduction occurs through an amiloride-sensitive sodium transport pathway. Science. 1984;223:403–5. 1984/01/27.CrossRefPubMed

13.

Huang AL, Chen X, Hoon MA, Chandrashekar J, Guo W, Trankner D et al. The cells and logic for mammalian sour taste detection. Nature. 2006/08/25. 2006;442:934–8. nature05084 [pii]https://doi.org/10.1038/nature05084.

14.

Chang RB, Waters H, Liman ER. A proton current drives action potentials in genetically identified sour taste cells. Proc Natl Acad Sci U S A. 2010/11/26. 2010;107:22320–5. 1013664107 [pii] https://doi.org/10.1073/pnas.1013664107

15.

Tu Y-H, Cooper AJ, Teng B, Chang RB, Artiga DJ, Turner HN, et al. An evolutionarily conserved gene family encodes proton-selective ion channels. Sci (80-). 2018;3264:eaao3264. https://doi.org/10.1126/science.aao3264.CrossRef

16.

Zhang J, Jin H, Zhang W, Ding C, O’Keeffe S, Ye M, et al. Sour sensing from the Tongue to the brain. Cell. 2019;179:392–e40215. https://doi.org/10.1016/j.cell.2019.08.031.CrossRefPubMed

17.

Teng B, Wilson CE, Tu YH, Joshi NR, Kinnamon SC, Liman ER. Cellular and neural responses to Sour Stimuli require the Proton Channel Otop1. Curr Biol. 2019;29:3647–e36565. https://doi.org/10.1016/j.cub.2019.08.077.CrossRefPubMedPubMedCentral

18.

Liang Z, Wilson CE, Teng B, Kinnamon SC, Liman ER. The proton channel OTOP1 is a sensor for the taste of ammonium chloride. Nat Commun. 2023;14.

19.

Saotome K, Teng B, Tsui CC (Alex), Lee WH, Tu YH, Kaplan JP Structures of the otopetrin proton channels Otop1 and Otop3, et al. editors. Nat Struct Mol Biol. 2019;26:518–25. https://doi.org/10.1038/s41594-019-0235-9

20.

Chandrashekar J, Kuhn C, Oka Y, Yarmolinsky DA, Hummler E, Ryba NJ, et al. The cells and peripheral representation of sodium taste in mice. Nat 2010/01/29. 2010;464:297–301. nature08783 [pii] https://doi.org/10.1038/nature08783.CrossRef

21.

Margolskee RF, Dyer J, Kokrashvili Z, Salmon KSH, Ilegems E, Daly K et al. T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proc Natl Acad Sci U S A. 2007/08/29. 2007;104:15075–80. https://doi.org/10.1073/pnas.0706678104

22.

Jang H-J, Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim B-J, Zhou J et al. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc Natl Acad Sci U S A. 2007/08/29. 2007;104:15069–74. https://doi.org/10.1073/pnas.0706890104

23.

Serrano J, Seflova J, Park J, Pribadi M, Sanematsu K, Shigemura N et al. The Ile191Val is a partial loss-of-function variant of the TAS1R2 sweet-taste receptor and is associated with reduced glucose excursions in humans. Mol Metab. 2021;54.

24.

Koehl A, Hu H, Feng D, Sun B, Zhang Y, Robertson MJ, et al. Structural insights into the activation of metabotropic glutamate receptors. Nature. 2019;566:79–84. https://doi.org/10.1038/s41586-019-0881-4.CrossRefPubMedPubMedCentral

25.

Park J, Selvam B, Sanematsu K, Shigemura N, Shukla D, Procko E. Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits. J Biol Chem. 2019;294:4759–74. https://doi.org/10.1074/jbc.RA118.006173.CrossRefPubMedPubMedCentral

26.

Jiang P, Cui M, Zhao B, Snyder LA, Benard LMJ, Osman R et al. Identification of the cyclamate interaction site within the transmembrane domain of the human sweet taste receptor subunit T1R3. J Biol Chem. 2005/08/04. 2005;280:34296–305. https://doi.org/10.1074/jbc.M505255200

27.

Koizumi A, Tsuchiya A, Nakajima K, -i., Ito K, Terada T, Shimizu-Ibuka A, et al. Human sweet taste receptor mediates acid-induced sweetness of miraculin. Proc Natl Acad Sci. 2011;108:16819–24. https://doi.org/10.1073/pnas.1016644108 2011/09/29.CrossRefPubMedPubMedCentral

28.

Nakajima K, Morita Y, Koizumi A, Asakura T, Terada T, Ito K et al. Acid-induced sweetness of neoculin is ascribed to its pH-dependent agonistic-antagonistic interaction with human sweet taste receptor. FASEB J. 2008/02/12. 2008;22:2323–30. fj.07-100289 [pii] https://doi.org/10.1096/fj.07-100289

29.

Nakajima K, Yokoyama K, Koizumi T, Koizumi A, Asakura T, Terada T, et al. Identification and modulation of the key amino acid residue responsible for the pH sensitivity of Neoculin, a taste-modifying protein. PLoS ONE. 2011;6:e19448. https://doi.org/10.1371/journal.pone.0019448PONE-D-11-02191. [pii]. 2011/05/12.CrossRefPubMedPubMedCentral

30.

Sanematsu K, Kitagawa M, Yoshida R, Nirasawa S, Shigemura N, Ninomiya Y. Intracellular acidification is required for full activation of the sweet taste receptor by miraculin. Sci Rep. 2016;6.

31.

Sanematsu K, Kusakabe Y, Shigemura N, Hirokawa T, Nakamura S, Imoto T, et al. Molecular mechanisms for sweet-suppressing effect of gymnemic acids. J Biol Chem. 2014;289:25711–20. https://doi.org/10.1074/jbc.M114.560409.CrossRefPubMedPubMedCentral

32.

Winnig M, Bufe B, Kratochwil NA, Slack JP, Meyerhof W. The binding site for neohesperidin dihydrochalcone at the human sweet taste receptor. BMC Struct Biol. 2007/10/16. 2007;7:66. https://doi.org/10.1186/1472-6807-7-66

33.

Nakagita T, Taketani C, Narukawa M, Hirokawa T, Kobayashi T, Misaka T. Ibuprofen, a nonsteroidal anti-inflammatory drug, is a potent inhibitor of the human Sweet taste receptor. Chem Senses. 2020;45:667–73. https://doi.org/10.1093/CHEMSE/BJAA057.CrossRefPubMed

34.

Nakagita T, Ishida A, Tachrim ZP, Wang L, Misaka T, Hashimoto M. Asymmetric synthesis of photophore-containing lactisole derivatives to elucidate sweet taste receptors. Molecules. 2020;25:1–25.CrossRef

35.

Nakagita T, Ishida A, Matsuya T, Kobayashi T, Narukawa M, Hirokawa T et al. M Behrens editor 2019 Structural insights into the differences among lactisole derivatives in inhibitory mechanisms against the human sweet taste receptor. PLoS ONE 14 https://doi.org/10.1371/journal.pone.0213552.

36.

Max M, Shanker YG, Huang L, Rong M, Liu Z, Campagne F et al. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat Genet. 2001/04/28. 2001;28:58–63. https://doi.org/10.1038/88270.

37.

Nakagita T, Matsuya T, Narukawa M, Kobayashi T, Hirokawa T, Misaka T. Modeling the structure of the transmembrane domain of T1R3, a subunit of the sweet taste receptor, with neohesperidin dihydrochalcone using molecular dynamics simulation. Biosci Biotechnol Biochem. 2023;87:1470–7. https://doi.org/10.1093/bbb/zbad133.CrossRefPubMed

38.

Zhang F, Klebansky B, Fine RM, Liu H, Xu H, Servant G et al. Molecular mechanism of the sweet taste enhancers. Proc Natl Acad Sci U S A. 2010/02/23. 2010;107:4752–7. https://doi.org/10.1073/pnas.0911660107

39.

Xu H, Staszewski L, Tang H, Adler E, Zoller M, Li X. Different functional roles of T1R subunits in the heteromeric taste receptors. Proc Natl Acad Sci U S A. 2004/09/09. 2004;101:14258–63. https://doi.org/10.1073/pnas.0404384101

40.

Servant G, Tachdjian C, Tang XQ, Werner S, Zhang F, Li X et al. Positive allosteric modulators of the human sweet taste receptor enhance sweet taste. Proc Natl Acad Sci U S A. 2010/02/23. 2010;107:4746–51. 0911670107 [pii] https://doi.org/10.1073/pnas.0911670107

41.

Zhang F, Klebansky B, Fine RM, Xu H, Pronin A, Liu H et al. Molecular mechanism for the umami taste synergism. Proc Natl Acad Sci U S A. 2008/12/24. 2008;105:20930–4.0810174106 [pii]https://doi.org/10.1073/pnas.0810174106

42.

Masuda K, Koizumi A, Nakajima K, Tanaka T, Abe K, Misaka T et al. Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. PLoS One. 2012/04/27. 2012;7:e35380. https://doi.org/10.1371/journal.pone.0035380

43.

Jiang P, Cui M, Zhao B, Liu Z, Snyder LA, Benard LM et al. Lactisole interacts with the transmembrane domains of human T1R3 to inhibit sweet taste. J Biol Chem. 2005/01/26. 2005;280:15238–46. M414287200 [pii] https://doi.org/10.1074/jbc.M414287200.

44.

Jiang P, Ji Q, Liu Z, Snyder LA, Benard LMJ, Margolskee RF, et al. The cysteine-rich region of T1R3 determines responses to intensely sweet proteins. J Biol Chem. 2004;279:45068–75. https://doi.org/10.1074/jbc.M406779200. 2004/08/10.CrossRefPubMed

45.

Galindo-Cuspinera V, Winnig M, Bufe B, Meyerhof W, Breslin PA. A TAS1R receptor-based explanation of sweet water-taste. Nature. 2006/04/25. 2006;441:354–7. nature04765 [pii] https://doi.org/10.1038/nature04765

46.

Zhang Y, Hoon MA, Chandrashekar J, Mueller KL, Cook B, Wu D, et al. Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 2003/02/13. 2003;112:293–301.https://doi.org/10.1016/S0092-8674(03)00071-0 [pii]CrossRef

47.

Hisatsune C, Yasumatsu K, Takahashi-Iwanaga H, Ogawa N, Kuroda Y, Yoshida R et al. Abnormal taste perception in mice lacking the type 3 inositol 1,4,5-trisphosphate receptor. J Biol Chem. 2007/10/11. 2007;282:37225–31. M705641200 [pii] https://doi.org/10.1074/jbc.M705641200

48.

Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, et al. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science. 2005;310:1495–9. https://doi.org/10.1126/science.1118435. 2005/12/03.CrossRefPubMed

49.

Taruno A, Vingtdeux V, Ohmoto M, Ma Z, Dvoryanchikov G, Li A et al. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature. 2013/03/08. 2013;495:223–6. nature11906 [pii] https://doi.org/10.1038/nature11906.

50.

Ma Z, Taruno A, Ohmoto M, Jyotaki M, Lim JC, Miyazaki H, et al. CALHM3 is essential for Rapid Ion Channel-mediated purinergic neurotransmission of GPCR-Mediated tastes. Neuron. 2018;98:547–e56110. https://doi.org/10.1016/j.neuron.2018.03.043.CrossRefPubMedPubMedCentral

51.

Feng X, Ambia J, Chen KYM, Young M, Barth P. Computational design of ligand-binding membrane receptors with high selectivity. Nat Chem Biol. 2017;13:715–23. https://doi.org/10.1038/nchembio.2371.CrossRefPubMedPubMedCentral

52.

Nuemket N, Yasui N, Kusakabe Y, Nomura Y, Atsumi N, Akiyama S, et al. Structural basis for perception of diverse chemical substances by T1r taste receptors. Nat Commun. 2017;8:15530. https://doi.org/10.1038/ncomms15530.CrossRefPubMedPubMedCentral

53.

Maillet EL, Margolskee RF, Mosinger B. Phenoxy herbicides and fibrates potently inhibit the human chemosensory receptor subunit T1R3. J Med Chem. 2009/10/13. 2009;52:6931–5. https://doi.org/10.1021/jm900823s

54.

Sanematsu K, Yamamoto M, Nagasato Y, Kawabata Y, Watanabe Y, Iwata S, et al. Prediction of dynamic allostery for the transmembrane domain of the sweet taste receptor subunit, TAS1R3. Commun Biol. 2023;6:340. https://doi.org/10.1038/s42003-023-04705-5.CrossRefPubMedPubMedCentral

55.

Audet M, Bouvier M. Restructuring G-Protein- Coupled Receptor Activation. Cell. 2012/10/02. 2012;151:14–23. https://doi.org/10.1016/j.cell.2012.09.003

56.

Schönegge A, Gallion J, Picard L, Wilkins AD, Le Gouill C, Audet M, et al. Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity. Nat Commun. 2017;8:2169. https://doi.org/10.1038/s41467-017-02257-x.CrossRefPubMedPubMedCentral

57.

Alhadeff R, Vorobyov I, Yoon HW, Warshel A. Exploring the free-energy landscape of GPCR activation. Proc Natl Acad Sci. 2018;115:10327–32. https://doi.org/10.1073/pnas.1810316115.CrossRefPubMedPubMedCentral

58.

Jacobson KA, Costanzi S, Paoletta S. Computational studies to predict or explain G protein coupled receptor polypharmacology. Trends Pharmacol Sci. 2014;35:658–63. https://doi.org/10.1016/j.tips.2014.10.009.CrossRefPubMedPubMedCentral

59.

Roth BL, Irwin JJ, Shoichet BK. Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol. 2017;13:1143–51. https://doi.org/10.1038/nchembio.2490.CrossRefPubMedPubMedCentral

60.

Yuan S, Filipek S, Palczewski K, Vogel H. Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway. Nat Commun 2014 51. 2014;5:1–10. https://doi.org/10.1038/ncomms5733.CrossRef

61.

Tizzano M, Gulbransen BD, Vandenbeuch A, Clapp TR, Herman JP, Sibhatu HM et al. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci U S A. 2010/02/06. 2010;107:3210–5. 0911934107 [pii] https://doi.org/10.1073/pnas.0911934107

62.

Saunders CJ, Christensen M, Finger TE, Tizzano M. Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation. Proc Natl Acad Sci U S A. 2014/04/09. 2014; 1402251111 [pii] https://doi.org/10.1073/pnas.1402251111.

63.

Lee RJ, Kofonow JM, Rosen PL, Siebert AP, Chen B, Doghramji L, et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J Clin Invest 2014/02/18. 2014;124:1393–405. 72094 [pii] https://doi.org/10.1172/JCI72094CrossRef

64.

Hanukoglu I, Hanukoglu A. Epithelial sodium channel (ENaC) family: phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene. 2016;579:95–132. https://doi.org/10.1016/j.gene.2015.12.061.CrossRefPubMedPubMedCentral

65.

Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A. Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways. Histochem Cell Biol. 2012;137:339–53.CrossRefPubMed

66.

Hughes I, Blasiole B, Huss D, Warchol ME, Rath NP, Hurle B, et al. Otopetrin 1 is required for otolith formation in the zebrafish Danio rerio. Dev Biol. 2004;276:391–402. https://doi.org/10.1016/j.ydbio.2004.09.001.CrossRefPubMedPubMedCentral

67.

Hurle B. Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1. Hum Mol Genet. 2003;12:777–89. https://doi.org/10.1093/hmg/ddg087.CrossRefPubMed

68.

Hughes I, Saito M, Schlesinger PH, Ornitz DM. Otopetrin 1 activation by purinergic nucleotides regulates intracellular calcium. Proc Natl Acad Sci U S A. 2007;104:12023–8. https://doi.org/10.1073/pnas.0705182104.CrossRefPubMedPubMedCentral

Title: Activation Dynamics for the Taste Receptor as an Energy Sensor
Authors: Keisuke Sanematsu
Noriatsu Shigemura
Publication date: 28-09-2024
Publisher: Springer International Publishing
Published in: Current Oral Health Reports / Issue 4/2024
Electronic ISSN: 2196-3002
DOI: https://doi.org/10.1007/s40496-024-00391-2

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Activation Dynamics for the Taste Receptor as an Energy Sensor

Abstract

Purpose of Review

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