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Mechanism of Kokumi Substance Perception: Role of Calcium-Sensing Receptor (CaSR) in Perceiving Kokumi Substances

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Book cover Koku in Food Science and Physiology

Abstract

Some foods are known to have flavor sensations, such as continuity, mouthfulness, and thick flavor, which cannot be explained by the five basic tastes alone. It has been demonstrated that these sensations are evoked by the addition of kokumi substances, which are flavor modifiers with no actual taste themselves. However, the mechanism is poorly understood. Investigation of the perception of amino acids and peptides revealed that γ-glutamyl-cysteinyl-glycine (GSH) was an agonist of calcium-sensing receptor (CaSR). Therefore, we hypothesized that CaSR was involved in perception of kokumi substances. In fact, all of the CaSR-activating substances we tested were effective as kokumi substances, and there was a positive correlation between CaSR activity and kokumi intensity of γ-glutamyl peptides. Furthermore, kokumi intensities of GSH and γ-Glu-Val-Gly, a potent kokumi peptide, were significantly reduced by a CaSR inhibitor, NPS-2143. These results suggest that CaSR is involved in the perception of kokumi substances.

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References

  • Amino Y, Nakazawa M, Kaneko M, Miyaki T, Miyamura N, Maruyama Y, Eto Y (2016) Structure-CaSR activity relation of kokumi γ-glutamyl peptides. Chem Pharm Bull 64:1181–1189

    Article  CAS  Google Scholar 

  • Bleasdale JE, Thakur NR, Gremban RS, Bundy GL, Fitzpatrick FA et al (1990) Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils. J Pharmacol Exp Ther 255:756–768

    PubMed  CAS  Google Scholar 

  • Broadhead GK, Mun HC, Avlani VA, Jourdan O, Church WB, Christopoulos A, Delbridge L, Conigrave AD (2011) Allosteric modulation of the calcium-sensing receptor by gamma-glutamyl peptides: inhibition of PTH secretion, suppression of intracellular cAMP levels, and a common mechanism of action with L-amino acids. J Biol Chem 286:8786–8797

    Article  CAS  Google Scholar 

  • Brown EM, MacLeod RJ (2001) Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 81:239–297

    Article  CAS  Google Scholar 

  • Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R et al (1993) Cloning and characterization of an extracellular Ca2+−sensing receptor from bovine parathyroid. Nature 366:575–580. EM

    Article  CAS  Google Scholar 

  • Bystrova MF, Romanov RA, Rogachevskaja OA, Churbanov GD, Kolesnikov SS (2010) Functional expression of the extracellular-Ca2+−sensing receptor in mouse taste cells. J Cell Sci 123:972–982

    Article  CAS  Google Scholar 

  • Caicedo A, Jafri MS, Roper SD (2000) In situ Ca2+ imaging reveals neurotransmitter receptors for glutamate in taste receptor cells. J Neurosci 20:7978–7985

    Article  CAS  Google Scholar 

  • Caicedo A, Kim KN, Roper SD (2002) Individual mouse taste cells respond to multiple chemical stimuli. J Physiol 544:501–509

    Article  CAS  Google Scholar 

  • Chattopadhyay N, Vassilev PM, Brown EM (1997) Calcium-sensing receptor: roles in and beyond systemic calcium homeostasis. Biol Chem 378:759–768

    PubMed  CAS  Google Scholar 

  • Chaudhari N, Roper SD (2010) The cell biology of taste. J Cell Biol 190:285–296

    Article  CAS  Google Scholar 

  • Cobb MH, Heagy W, Danner J, Lenhoff HM, Marshall GR (1982) Structural and conformational properties of peptides interacting with the glutathione receptor of hydra. Mol Pharmacol 21:629–631

    PubMed  CAS  Google Scholar 

  • Conigrave AD, Hampson DR (2006) Broad-spectrum L-amino acid sensing by class 3 G-protein-coupled receptors. Trends Endocrinol Metab 17:398–407

    Article  CAS  Google Scholar 

  • Conigrave AD, Quinn SJ, Brown EM (2000) L-amino acid sensing by the extracellular Ca2+ − sensing receptor. Proc Natl Acad Sci U S A 97:4814–4819

    Article  CAS  Google Scholar 

  • Dando R, Roper SD (2009) Cell-to-cell communication in intact taste buds through ATP signalling from pannexin 1 gap junction hemichannels. J Physiol 587:5899–5906

    Article  CAS  Google Scholar 

  • De Craecker S, Verbruggen C, Rajan PK, Smith K, Haemers A, Fairlamb A (1997) Characterization of the peptide substrate specificity of glutathionylspermidine synthetase from Crithidia fasciculata. Mol Biochem Parasitol 84:25–32

    Article  Google Scholar 

  • DeFazio RA, Dvoryanchikov G, Maruyama Y, Kim JW, Pereira E et al (2006) Separate populations of receptor cells and presynaptic cells in mouse taste buds. J Neurosci 26:3971–3980

    Article  CAS  Google Scholar 

  • Dunkel A, Koster J, Hofmann T (2007) Molecular and sensory characterization of gamma-glutamyl peptides as key contributors to the kokumi taste of edible beans (Phaseolus vulgaris L.). J Agric Food Chem 55:6712–6719

    Article  CAS  Google Scholar 

  • Dvoryanchikov G, Tomchik SM, Chaudhari N (2007) Biogenic amine synthesis and uptake in rodent taste buds. J Comp Neurol 505:302–313

    Article  CAS  Google Scholar 

  • Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ et al (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310:1495–1499

    Article  CAS  Google Scholar 

  • Gowen M, Stroup GB, Dodds RA, James IE, Votta BJ et al (2000) Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest 105:1595–1604

    Article  CAS  Google Scholar 

  • Helmchen G (2000) In: Yuste R, Lanni F, Konnerth A (eds) Calibration of fluorescent calcium indicators. Cold Spring Harbor Laboratory, Cold Spring Harbor

    Google Scholar 

  • Hirayama A, Igarashi K, Tomita M, Soga T (2014) Development of quantitative method for determination of γ-glutamyl peptides by capillary electrophoresis tandem mass spectrometry: an efficient approach avoiding matrix effect. J Chromatogr 1369:161–169

    Article  CAS  Google Scholar 

  • Huang L, Shanker YG, Dubauskaite J, Zheng JZ, Yan W et al (1999) Ggamma13 colocalizes with gustducin in taste receptor cells and mediates IP3 responses to bitter denatonium. Nat Neurosci 2:1055–1062

    Article  CAS  Google Scholar 

  • Huang YJ, Maruyama Y, Lu KS, Pereira E, Plonsky I et al (2005) Mouse taste buds use serotonin as a neurotransmitter. J Neurosci 25:843–847

    Article  CAS  Google Scholar 

  • Huang AL, Chen X, Hoon MA, Chandrashekar J, Guo W et al (2006) The cells and logic for mammalian sour taste detection. Nature 442:934–938

    Article  CAS  Google Scholar 

  • Huang YJ, Maruyama Y, Dvoryanchikov G, Pereira E, Chaudhari N et al (2007) The role of pannexin 1 hemichannels in ATP release and cell-cell communication in mouse taste buds. Proc Natl Acad Sci U S A 104:6436–6441

    Article  CAS  Google Scholar 

  • Huang YA, Maruyama Y, Stimac R, Roper SD (2008) Presynaptic (type III) cells in mouse taste buds sense sour (acid) taste. J Physiol 586:2903–2912

    Article  CAS  Google Scholar 

  • Iwatsuki K, Ichikawa R, Hiasa M, Moriyama Y, Torii K et al (2009) Identification of the vesicular nucleotide transporter (VNUT) in taste cells. Biochem Biophys Res Commun 388:1–5

    Article  CAS  Google Scholar 

  • Kinnamon JC, Taylor BJ, Delay RJ, Roper SD (1985) Ultrastructure of mouse vallate taste buds. I. Taste cells and their associated synapses. J Comp Neurol 235:48–60

    Article  CAS  Google Scholar 

  • Leslie EM, Bowers RJ, Deely RG, Cole SPC (2003) Structural requirements for functional interaction of glutathione tripeptide analogs with the human multidrug resistance protein 1 (MRP1). J Pharmacol Exp Ther 304:643–653

    Article  CAS  Google Scholar 

  • Li X, Staszewski L, Xu H, Durick K, Zoller M et al (2002) Human receptors for sweet and umami taste. Proc Natl Acad Sci U S A 99:4692–4696

    Article  CAS  Google Scholar 

  • Maruyama Y, Pereira E, Margolskee RF, Chaudhari N, Roper SD (2006) Umami responses in mouse taste cells indicate more than one receptor. J Neurosci 26:2227–2234

    Article  CAS  Google Scholar 

  • Maruyama Y, Yasuda R, Kuroda M, Eto Y (2012) Kokumi substances, enhancers of basic tastes, induce responses in calcium-sensing receptor expressing taste cells. PLoS One 7:e34489

    Article  CAS  Google Scholar 

  • McCaughey SA, Forestell CA, Tordoff MG (2005) Calcium deprivation increases the palatability of calcium solutions in rats. Physiol Behav 84:335–342

    Article  CAS  Google Scholar 

  • Medler KF, Margolskee RF, Kinnamon SC (2003) Electrophysiological characterization of voltage-gated currents in defined taste cell types of mice. J Neurosci 23:2608–2617

    Article  CAS  Google Scholar 

  • Michlig S, Damak S, Le Coutre J (2007) Claudin-based permeability barriers in taste buds. J Comp Neurol 502:1003–1011

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Murray RG (1993) Cellular relations in mouse circumvallate taste buds. Microsc Res Tech 26:209–224

    Article  CAS  Google Scholar 

  • Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ et al (2001) Mammalian sweet taste receptors. Cell 106:381–390

    Article  CAS  Google Scholar 

  • Nelson G, Chandrashekar J, Hoon MA, Feng L, Zhao G et al (2002) An amino-acid taste receptor. Nature 416:199–202

    Article  CAS  Google Scholar 

  • Ninomiya Y, Tonosaki K, Funakoshi M (1982) Gustatory neural response in the mouse. Brain Res 244:370–373

    Article  CAS  Google Scholar 

  • Nofre G, Tinti JM, Chatzopoulos FO (1987) Sweetening agents. US patent 4921939

    Google Scholar 

  • Ogura T, Kinnamon SC (1999) IP(3)-independent release of Ca2+ from intracellular stores: a novel mechanism for transduction of bitter stimuli. J Neurophysiol 82:2657–2666

    Article  CAS  Google Scholar 

  • Ohsu T, Amino Y, Nagasaki H, Yamanaka T, Takeshita S et al (2010) Involvement of the calcium-sensing receptor in human taste perception. J Biol Chem 285:1016–1022

    Article  CAS  Google Scholar 

  • Richter TA, Dvoryanchikov GA, Chaudhari N, Roper SD (2004) Acid-sensitive two-pore domain potassium (K2P) channels in mouse taste buds. J Neurophysiol 92:1928–1936

    Article  CAS  Google Scholar 

  • Roberts CD, Dvoryanchikov G, Roper SD, Chaudhari N (2009) Interaction between the second messengers cAMP and Ca2+ in mouse presynaptic taste cells. J Physiol 587:1657–1668

    Article  CAS  Google Scholar 

  • Rodriguez M, Nemeth E, Martin D (2005) The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol 288:F253–F264

    Article  CAS  Google Scholar 

  • Romanov RA, Rogachevskaja OA, Bystrova MF, Jiang P, Margolskee RF et al (2007) Afferent neurotransmission mediated by hemichannels in mammalian taste cells. EMBO J 26:657–667

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Rybczynska A, Lehmann A, Jurska-Jasko A, Boblewski K, Orlewska C et al (2006) Hypertensive effect of calcilytic NPS 2143 administration in rats. J Endocrinol 191:189–195

    Article  CAS  Google Scholar 

  • Salari H, Bramley A, Langlands J, Howard S, Chan-Yeung M et al (1993) Effect of phospholipase C inhibitor U-73122 on antigen-induced airway smooth muscle contraction in Guinea pigs. Am J Respir Cell Mol Biol 9:405–410

    Article  CAS  Google Scholar 

  • San Gabriel A, Uneyama H, Maekawa T, Torii K (2009) The calcium-sensing receptor in taste tissue. Biochem Biophys Res Commun 378:414–418

    Article  CAS  Google Scholar 

  • Thompson AK, Mostafapour SP, Denlinger LC, Bleasdale JE, Fisher SK (1991) The aminosteroid U-73122 inhibits muscarinic receptor sequestration and phosphoinositide hydrolysis in SK-N-SH neuroblastoma cells. A role for Gp in receptor compartmentation. J Biol Chem 266:23856–23862

    PubMed  CAS  Google Scholar 

  • Toelstede S, Hofmann T (2009) Kokumi-active glutamyl peptides in cheeses and their biogeneration by Penicillium roquefortii. J Agric Food Chem 57:3738–3748

    Article  CAS  Google Scholar 

  • Tomchik SM, Berg S, Kim JW, Chaudhari N, Roper SD (2007) Breadth of tuning and taste coding in mammalian taste buds. J Neurosci 27:10840–10848

    Article  CAS  Google Scholar 

  • Tordoff MG, Shao H, Alarcon LK, Margolskee RF, Mosinger B et al (2008) Involvement of T1R3 in calcium-magnesium taste. Physiol Genomics 34:338–348

    Article  CAS  Google Scholar 

  • Ueda Y, Sakaguchi M, Hirayama K, Miyajima R, Kimizuka A (1990) Characteristic flavor constituents in water extract of garlic. Agric Biol Chem 54:163–169

    CAS  Google Scholar 

  • Ueda Y, Tsubuku T, Miyajima R (1994) Composition of sulfur-containing components in onion and their flavor characters. Biosci Biotechnol Biochem 58:108–110

    Article  CAS  Google Scholar 

  • Ueda T, Yonemitsu M, Tsubuku T, Sakaguchi M, Miyajima R (1997) Flavor characteristics of glutathione in raw and cooked foodstuffs. Biosci Biotechnol Biochem 61:1977–1980

    Article  CAS  Google Scholar 

  • Wang M, Yao Y, Kuang D, Hampson DR (2006) Activation of family C G-protein-coupled receptors by the tripeptide glutathione. J Biol Chem 281:8864–8870

    Article  CAS  Google Scholar 

  • Yee CL, Yang R, Bottger B, Finger TE, Kinnamon JC (2001) “Type III” cells of rat taste buds: immunohistochemical and ultrastructural studies of neuron-specific enolase, protein gene product 9.5, and serotonin. J Comp Neurol 440:97–108

    Article  CAS  Google Scholar 

  • Zhang Y, Hoon MA, Chandrashekar J, Mueller KL, Cook B et al (2003) Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 112:293–301

    Article  CAS  Google Scholar 

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Acknowledgments

We sincerely thank Dr. Kiyoshi Miwa, Dr. Tohru Kouda, Dr. Toshihisa Kato, Naohiro Miyamura, and Dr. Yuzuru Eto of Ajinomoto Co., Inc., for their encouragement and continued support of this work. We also thank Dr. Ken Iwatsuki, Dr. Hisayuki Uneyama, and Dr. Kunio Torii for providing the antibodies and for valuable suggestions. We thank Takeaki Ohsu, Sen Takeshita, Reiko Yasuda, and Fumie Futaki for their technical assistance on CaSR activity assay. We thank Dr. Yusuke Amino, Dr. Masakazu Nakazawa, Yuki Tahara, Megumi Kaneko, and Toshihiro Hatanaka for synthesis of peptides. We are grateful to Hiroaki Nagasaki, Tomohiko Yamanaka, Fusataka Kenmotsu, Takashi Miyaki, and Takaho Tajima for conducting sensory evaluation. We are also grateful to the panelists who have participated on the sensory evaluation.

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Correspondence to Motonaka Kuroda .

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Maruyama, Y., Kuroda, M. (2019). Mechanism of Kokumi Substance Perception: Role of Calcium-Sensing Receptor (CaSR) in Perceiving Kokumi Substances. In: Nishimura, T., Kuroda, M. (eds) Koku in Food Science and Physiology. Springer, Singapore. https://doi.org/10.1007/978-981-13-8453-0_8

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