Endocrinol Metab.  2014 Mar;29(1):12-19. 10.3803/EnM.2014.29.1.12.

Sweet Taste-Sensing Receptors Expressed in Pancreatic beta-Cells: Sweet Molecules Act as Biased Agonists

• Kojima I
• Nakagawa Y
• Ohtsu Y
• Medina A
• Nagasawa M

• KMID: 2169346
• DOI: http://doi.org/10.3803/EnM.2014.29.1.12

Abstract

The sweet taste receptors present in the taste buds are heterodimers comprised of T1R2 and T1R3. This receptor is also expressed in pancreatic beta-cells. When the expression of receptor subunits is determined in beta-cells by quantitative reverse transcription polymerase chain reaction, the mRNA expression level of T1R2 is extremely low compared to that of T1R3. In fact, the expression of T1R2 is undetectable at the protein level. Furthermore, knockdown of T1R2 does not affect the effect of sweet molecules, whereas knockdown of T1R3 markedly attenuates the effect of sweet molecules. Consequently, a homodimer of T1R3 functions as a receptor sensing sweet molecules in beta-cells, which we designate as sweet taste-sensing receptors (STSRs). Various sweet molecules activate STSR in beta-cells and augment insulin secretion. With regard to intracellular signals, sweet molecules act on STSRs and increase cytoplasmic Ca2+ and/or cyclic AMP (cAMP). Specifically, when an STSR is stimulated by one of four different sweet molecules (sucralose, acesulfame potassium, sodium saccharin, or glycyrrhizin), distinct signaling pathways are activated. Patterns of changes in cytoplasmic Ca2+ and/or cAMP induced by these sweet molecules are all different from each other. Hence, sweet molecules activate STSRs by acting as biased agonists.

Keyword

beta-Cell; Insulin; Sweet taste receptor; Biased agonist; Calcium; Cyclic AMP

MeSH Terms

Bias (Epidemiology)*
Calcium
Cyclic AMP
Cytoplasm
Insulin
Polymerase Chain Reaction
Potassium
Reverse Transcription
RNA, Messenger
Saccharin
Sodium
Taste Buds
Calcium
Cyclic AMP
Insulin
Potassium
RNA, Messenger
Saccharin
Sodium

Figure

• 

  Fig. 1 Comparison of (A) the sweet taste receptor in taste cells and (B) the sweet taste-sensing receptor in β-cells. The sweet taste receptor expressed in taste cells of the taste bud (left) is a heterodimer comprised of T1R2 and T1R3, whereas the sweet taste-sensing receptor expressed in β-cells (right) is a homodimer of T1R3.

• 

  Fig. 2 Comparison of the effects of four sweeteners on [Ca2+]c and [cyclic AMP, cAMP]c. MIN6 cells were stimulated by (A) 50-mM acesulfame-K, (B) 50-mM sucralose, (C) 3-mM dipotassium glycyrrhizinate (DPG), or (D) 50-mM saccharin-Na as indicated by the arrows. Changes in [Ca2+]c (○) and [cAMP]c (●) were monitored.

• 

  Fig. 3 Schematic presentation of the actions of the four sweeteners. Signaling cascades activated by (A) acesulfame-K, (B) sucralose, (C) dipotassium glycyrrhizinate (DPG), and (D) saccharin-Na are shown. When the colors of the G proteins and channels are different, it means that the molecules are different. AC, adenylyl cyclase; PLC, phospholipase C; αS, α-subunit of Gs; αX, α-subunit of YM254890-sensitive G protein; αY, α-subunit of YM254890-insensitive G protein; ATP, adenosine triphosphate; cAMP, cyclic AMP; PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; DAG, diacylglycerol; INsP3, inositol 1,4,5-tripsphophate.

Reference

1. Bachmanov AA, Li X, Reed DR, Ohmen JD, Li S, Chen Z, Tordoff MG, de Jong PJ, Wu C, West DB, Chatterjee A, Ross DA, Beauchamp GK. Positional cloning of the mouse saccharin preference (Sac) locus. Chem Senses. 2001; 26:925–933.

2. Li X, Inoue M, Reed DR, Huque T, Puchalski RB, Tordoff MG, Ninomiya Y, Beauchamp GK, Bachmanov AA. High-resolution genetic mapping of the saccharin preference locus (Sac) and the putative sweet taste receptor (T1R1) gene (Gpr70) to mouse distal Chromosome 4. Mamm Genome. 2001; 12:13–16.

3. Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell. 2001; 106:381–390.

4. Kitagawa M, Kusakabe Y, Miura H, Ninomiya Y, Hino A. Molecular genetic identification of a candidate receptor gene for sweet taste. Biochem Biophys Res Commun. 2001; 283:236–242.

5. Max M, Shanker YG, Huang L, Rong M, Liu Z, Campagne F, Weinstein H, Damak S, Margolskee RF. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat Genet. 2001; 28:58–63.

6. Montmayeur JP, Liberles SD, Matsunami H, Buck LB. A candidate taste receptor gene near a sweet taste locus. Nat Neurosci. 2001; 4:492–498.

7. Zhang Y, Hoon MA, Chandrashekar J, Mueller KL, Cook B, Wu D, Zuker CS, Ryba NJ. Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell. 2003; 112:293–301.

8. Zhao GQ, Zhang Y, Hoon MA, Chandrashekar J, Erlenbach I, Ryba NJ, Zuker CS. The receptors for mammalian sweet and umami taste. Cell. 2003; 115:255–266.

9. 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; 99:4692–4696.

10. Temussi P. The sweet taste receptor: a single receptor with multiple sites and modes of interaction. Adv Food Nutr Res. 2007; 53:199–239.

11. Damak S, Rong M, Yasumatsu K, Kokrashvili Z, Varadarajan V, Zou S, Jiang P, Ninomiya Y, Margolskee RF. Detection of sweet and umami taste in the absence of taste receptor T1r3. Science. 2003; 301:850–853.

12. McLaughlin SK, McKinnon PJ, Margolskee RF. Gustducin is a taste-cell-specific G protein closely related to the transducins. Nature. 1992; 357:563–569.

13. Rössler P, Kroner C, Freitag J, Noe J, Breer H. Identification of a phospholipase C beta subtype in rat taste cells. Eur J Cell Biol. 1998; 77:253–261.

14. Prawitt D, Monteilh-Zoller MK, Brixel L, Spangenberg C, Zabel B, Fleig A, Penner R. TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i. Proc Natl Acad Sci U S A. 2003; 100:15166–15171.

15. Taruno A, Vingtdeux V, Ohmoto M, Ma Z, Dvoryanchikov G, Li A, Adrien L, Zhao H, Leung S, Abernethy M, Koppel J, Davies P, Civan MM, Chaudhari N, Matsumoto I, Hellekant G, Tordoff MG, Marambaud P, Foskett JK. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature. 2013; 495:223–226.

16. Ruiz CJ, Wray K, Delay E, Margolskee RF, Kinnamon SC. Behavioral evidence for a role of alpha-gustducin in glutamate taste. Chem Senses. 2003; 28:573–579.

17. He W, Yasumatsu K, Varadarajan V, Yamada A, Lem J, Ninomiya Y, Margolskee RF, Damak S. Umami taste responses are mediated by alpha-transducin and alpha-gustducin. J Neurosci. 2004; 24:7674–7680.

18. Trubey KR, Culpepper S, Maruyama Y, Kinnamon SC, Chaudhari N. Tastants evoke cAMP signal in taste buds that is independent of calcium signaling. Am J Physiol Cell Physiol. 2006; 291:C237–C244.

19. Temussi PA. Why are sweet proteins sweet? Interaction of brazzein, monellin and thaumatin with the T1R2-T1R3 receptor. FEBS Lett. 2002; 526:1–4.

20. Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S, Jingami H, Morikawa K. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature. 2000; 407:971–977.

21. 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; 101:14258–14263.

22. Cui M, Jiang P, Maillet E, Max M, Margolskee RF, Osman R. The heterodimeric sweet taste receptor has multiple potential ligand binding sites. Curr Pharm Des. 2006; 12:4591–4600.

23. Masuda K, Koizumi A, Nakajima K, Tanaka T, Abe K, Misaka T, Ishiguro M. Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. PLoS One. 2012; 7:e35380.

24. Jiang P, Cui M, Zhao B, Snyder LA, Benard LM, Osman R, Max M, Margolskee RF. Identification of the cyclamate interaction site within the transmembrane domain of the human sweet taste receptor subunit T1R3. J Biol Chem. 2005; 280:34296–34305.

25. Galindo-Cuspinera V, Winnig M, Bufe B, Meyerhof W, Breslin PA. A TAS1R receptor-based explanation of sweet 'water-taste'. Nature. 2006; 441:354–357.

26. Jiang P, Ji Q, Liu Z, Snyder LA, Benard LM, Margolskee RF, Max M. The cysteine-rich region of T1R3 determines responses to intensely sweet proteins. J Biol Chem. 2004; 279:45068–45075.

27. Masuda T, Taguchi W, Sano A, Ohta K, Kitabatake N, Tani F. Five amino acid residues in cysteine-rich domain of human T1R3 were involved in the response for sweet-tasting protein, thaumatin. Biochimie. 2013; 95:1502–1505.

28. Dyer J, Salmon KS, Zibrik L, Shirazi-Beechey SP. Expression of sweet taste receptors of the T1R family in the intestinal tract and enteroendocrine cells. Biochem Soc Trans. 2005; 33(Pt 1):302–305.

29. Bezençon C, le Coutre J, Damak S. Taste-signaling proteins are coexpressed in solitary intestinal epithelial cells. Chem Senses. 2007; 32:41–49.

30. Kojima I, Nakagawa Y. The role of the sweet taste receptor in enteroendocrine cells and pancreatic beta-cells. Diabetes Metab J. 2011; 35:451–457.

31. Ren X, Zhou L, Terwilliger R, Newton SS, de Araujo IE. Sweet taste signaling functions as a hypothalamic glucose sensor. Front Integr Neurosci. 2009; 3:12.

32. Masubuchi Y, Nakagawa Y, Ma J, Sasaki T, Kitamura T, Yamamoto Y, Kurose H, Kojima I, Shibata H. A novel regulatory function of sweet taste-sensing receptor in adipogenic differentiation of 3T3-L1 cells. PLoS One. 2013; 8:e54500.

33. Elliott RA, Kapoor S, Tincello DG. Expression and distribution of the sweet taste receptor isoforms T1R2 and T1R3 in human and rat bladders. J Urol. 2011; 186:2455–2462.

34. Tizzano M, Cristofoletti M, Sbarbati A, Finger TE. Expression of taste receptors in solitary chemosensory cells of rodent airways. BMC Pulm Med. 2011; 11:3.

35. Nakagawa Y, Nagasawa M, Yamada S, Hara A, Mogami H, Nikolaev VO, Lohse MJ, Shigemura N, Ninomiya Y, Kojima I. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion. PLoS One. 2009; 4:e5106.

36. Kyriazis GA, Soundarapandian MM, Tyrberg B. Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proc Natl Acad Sci U S A. 2012; 109:E524–E532.

37. Nakagawa Y, Nagasawa M, Mogami H, Lohse M, Ninomiya Y, Kojima I. Multimodal function of the sweet taste receptor expressed in pancreatic beta-cells: generation of diverse patterns of intracellular signals by sweet agonists. Endocr J. 2013; 60:1191–1206.

38. Tordoff MG, Alarcon LK, Valmeki S, Jiang P. T1R3: a human calcium taste receptor. Sci Rep. 2012; 2:496.

39. Imoto T, Miyasaka A, Ishima R, Akasaka K. A novel peptide isolated from the leaves of Gymnema sylvestre. I. Characterization and its suppressive effect on the neural responses to sweet taste stimuli in the rat. Comp Biochem Physiol A Comp Physiol. 1991; 100:309–314.

40. Nakagawa Y, Ohtsu Y, Nagasawa M, Shibata H, Kojima I. Glucose promotes its own metabolism by acting on the cell-surface glucose-sensing receptor T1R3. Endocr J. 2013; 11. 07. Epub DOI: http://dx.doi.org/10.1507/endocrj.EJ13-0431.

41. Furman B, Ong WK, Pyne NJ. Cyclic AMP signaling in pancreatic islets. Adv Exp Med Biol. 2010; 654:281–304.

42. Cali JJ, Zwaagstra JC, Mons N, Cooper DM, Krupinski J. Type VIII adenylyl cyclase. A Ca2+/calmodulin-stimulated enzyme expressed in discrete regions of rat brain. J Biol Chem. 1994; 269:12190–12195.

43. Kenakin TP. Biased signalling and allosteric machines: new vistas and challenges for drug discovery. Br J Pharmacol. 2012; 165:1659–1669.

44. Roper SD. Signal transduction and information processing in mammalian taste buds. Pflugers Arch. 2007; 454:759–776.