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Xylitol stimulates saliva secretion via muscarinic receptor signaling pathway

  • Park, Eunjoo (Department of Oral Microbiology, School of Dentistry, Pusan National University) ;
  • Na, Hee Sam (Department of Oral Microbiology, School of Dentistry, Pusan National University) ;
  • Jeong, Sunghee (Department of Oral Medicine, School of Dentistry, Pusan National University) ;
  • Chung, Jin (Department of Oral Microbiology, School of Dentistry, Pusan National University)
  • Received : 2019.06.11
  • Accepted : 2019.06.17
  • Published : 2019.06.30

Abstract

Xylitol is well-known to have an anti-caries effect by inhibiting the replication of cariogenic bacteria. In addition, xylitol enhances saliva secretion. However, the precise molecular mechanism of xylitol on saliva secretion is yet to be elucidated. Thus, in this study, we aimed to investigate the stimulatory effect of xylitol on saliva secretion and to further evaluate the involvement of xylitol in muscarinic type 3 receptor (M3R) signaling. For determining these effects, we measured the saliva flow rate following xylitol treatment in healthy individuals and patients with dry mouth. We further tested the effects of xylitol on M3R signaling in human salivary gland (HSG) cells using real-time quantitative reverse-transcriptase polymerase chain reaction, immunoblotting, and immunostaining. Xylitol candy significantly increased the salivary flow rate and intracellular calcium release in HSG cells via the M3R signaling pathway. In addition, the expressions of M3R and aquaporin 5 were induced by xylitol treatment. Lastly, we investigated the distribution of M3R and aquaporin 5 in HSG cells. Xylitol was found to activate M3R, thereby inducing increases in $Ca^{2+}$ concentration. Stimulation of the muscarinic receptor induced by xylitol activated the internalization of M3R and subsequent trafficking of aquaporin 5. Taken together, these findings suggest a molecular mechanism for secretory effects of xylitol on salivary epithelial cells.

Acknowledgement

Supported by : national Research Foundation of Korea

References

  1. Putney JW Jr. Identification of cellular activation mechanisms associated with salivary secretion. Annu Rev Physiol 1986;48:75-88. doi: 10.1146/annurev.ph.48.030186.000451. https://doi.org/10.1146/annurev.ph.48.030186.000451
  2. Dawson LJ, Stanbury J, Venn N, Hasdimir B, Rogers SN, Smith PM. Antimuscarinic antibodies in primary Sjogren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells. Arthritis Rheum 2006;54:1165-73. doi: 10.1002/art.21764. https://doi.org/10.1002/art.21764
  3. Nakamura T, Matsui M, Uchida K, Futatsugi A, Kusakawa S, Matsumoto N, Nakamura K, Manabe T, Taketo MM, Mikoshiba K. M(3) muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J Physiol 2004;558(Pt 2):561-75. doi: 10.1113/jphysiol.2004.064626. https://doi.org/10.1113/jphysiol.2004.064626
  4. Hattori T, Wang PL. Calcium antagonists cause dry mouth by inhibiting resting saliva secretion. Life Sci 2007;81:683-90. doi: 10.1016/j.lfs.2007.07.005. https://doi.org/10.1016/j.lfs.2007.07.005
  5. Ma T, Song Y, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J Biol Chem 1999;274:20071-4. doi: 10.1074/jbc.274.29.20071. https://doi.org/10.1074/jbc.274.29.20071
  6. Napenas JJ, Brennan MT, Fox PC. Diagnosis and treatment of xerostomia (dry mouth). Odontology 2009;97:76-83. doi:10.1007/s10266-008-0099-7. https://doi.org/10.1007/s10266-008-0099-7
  7. Cassolato SF, Turnbull RS. Xerostomia: clinical aspects and treatment. Gerodontology 2003;20:64-77. doi: 10.1111/j.1741-2358.2003.00064.x. https://doi.org/10.1111/j.1741-2358.2003.00064.x
  8. Shiboski CH, Hodgson TA, Ship JA, Schiodt M. Management of salivary hypofunction during and after radiotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103 Suppl:S66.e1-19. doi: 10.1016/j.tripleo.2006.11.013. https://doi.org/10.1016/j.tripleo.2006.05.023
  9. von Bultzingslowen I, Sollecito TP, Fox PC, Daniels T, Jonsson R, Lockhart PB, Wray D, Brennan MT, Carrozzo M, Gandera B, Fujibayashi T, Navazesh M, Rhodus NL, Schiodt M. Salivary dysfunction associated with systemic diseases: systematic review and clinical management recommendations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103 Suppl:S57.e1-15. doi: 10.1016/j.tripleo.2006.11.010.
  10. Lynch H, Milgrom P. Xylitol and dental caries: an overview for clinicians. J Calif Dent Assoc 2003;31:205-9.
  11. Tanzer JM. Xylitol chewing gum and dental caries. Int Dent J 1995;45(1 Suppl 1):65-76.
  12. Han SJ, Jeong SY, Nam YJ, Yang KH, Lim HS, Chung J. Xylitol inhibits inflammatory cytokine expression induced by lipopolysaccharide from Porphyromonas gingivalis. Clin Diagn Lab Immunol 2005;12:1285-91. doi: 10.1128/CDLI.12.11.1285-1291.2005.
  13. Odusola F. Chewing gum as aid in treatment of hyposalivation. N Y State Dent J 1991;57:28-31.
  14. Popova JS, Rasenick MM. Clathrin-mediated endocytosis of m3 muscarinic receptors. Roles for Gbetagamma and tubulin. J Biol Chem 2004;279:30410-8. doi: 10.1074/jbc.M402871200. https://doi.org/10.1074/jbc.M402871200
  15. Scarselli M, Donaldson JG. Constitutive internalization of G protein-coupled receptors and G proteins via clathrin-independent endocytosis. J Biol Chem 2009;284:3577-85. doi:10.1074/jbc.M806819200. https://doi.org/10.1074/jbc.M806819200
  16. Gautam D, Heard TS, Cui Y, Miller G, Bloodworth L, Wess J. Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and doubleknockout mice. Mol Pharmacol 2004;66:260-7. doi: 10.1124/mol.66.2.260. https://doi.org/10.1124/mol.66.2.260
  17. Nagy K, Szlavik V, Racz G, Ovari G, Vag J, Varga G. Human submandibular gland (HSG) cell line as a model for studying salivary gland Ca2+ signalling mechanisms. Acta Physiol Hung 2007;94:301-13. doi: 10.1556/APhysiol.94.2007.4.2. https://doi.org/10.1556/APhysiol.94.2007.4.2
  18. Melvin JE, Yule D, Shuttleworth T, Begenisich T. Regulation of fluid and electrolyte secretion in salivary gland acinar cells. Annu Rev Physiol 2005;67:445-69. doi: 10.1146/annurev. physiol.67.041703.084745. https://doi.org/10.1146/annurev.physiol.67.041703.084745
  19. Jin M, Hwang SM, Davies AJ, Shin Y, Bae JS, Lee JH, Lee EB, Song YW, Park K. Autoantibodies in primary Sjogren's syndrome patients induce internalization of muscarinic type 3 receptors. Biochim Biophys Acta 2012;1822:161-7. doi:10.1016/j.bbadis.2011.11.012. https://doi.org/10.1016/j.bbadis.2011.11.012
  20. Asari T, Maruyama K, Kusama H. Salivation triggered by pilocarpine involves aquaporin-5 in normal rats but not in irradiated rats. Clin Exp Pharmacol Physiol 2009;36:531-8. doi:10.1111/j.1440-1681.2008.05104.x. https://doi.org/10.1111/j.1440-1681.2008.05104.x
  21. Murakami M, Murdiastuti K, Hosoi K, Hill AE. AQP and the control of fluid transport in a salivary gland. J Membr Biol 2006;210:91-103. doi: 10.1007/s00232-005-0848-2. https://doi.org/10.1007/s00232-005-0848-2
  22. Wang D, Iwata F, Muraguchi M, Ooga K, Ohmoto Y, Takai M, Mori T, Ishikawa Y. Correlation between salivary secretion and salivary AQP5 levels in health and disease. J Med Invest 2009;56 Suppl:350-3. doi: 10.2152/jmi.56.350. https://doi.org/10.2152/jmi.56.350
  23. Krane CM, Melvin JE, Nguyen HV, Richardson L, Towne JE, Doetschman T, Menon AG. Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation. J Biol Chem 2001;276:23413-20. doi: 10.1074/jbc.M008760200. https://doi.org/10.1074/jbc.M008760200
  24. Shi L, Cong X, Zhang Y, Ding C, Ding QW, Fu FY, Wu LL, Yu GY. Carbachol improves secretion in the early phase after rabbit submandibular gland transplantation. Oral Dis 2010;16:351-9. doi: 10.1111/j.1601-0825.2009.01633.x. https://doi.org/10.1111/j.1601-0825.2009.01633.x
  25. Tsubota K, Hirai S, King LS, Agre P, Ishida N. Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjogren's syndrome. Lancet 2001;357:688-9. doi: 10.1016/S0140-6736(00)04140-4. https://doi.org/10.1016/S0140-6736(00)04140-4
  26. Gresz V, Kwon TH, Gong H, Agre P, Steward MC, King LS, Nielsen S. Immunolocalization of AQP-5 in rat parotid and submandibular salivary glands after stimulation or inhibition of secretion in vivo. Am J Physiol Gastrointest Liver Physiol 2004;287:G151-61. doi: 10.1152/ajpgi.00480.2003. https://doi.org/10.1152/ajpgi.00480.2003
  27. Li Z, Zhao D, Gong B, Xu Y, Sun H, Yang B, Zhao X. Decreased saliva secretion and down-regulation of AQP5 in submandibular gland in irradiated rats. Radiat Res 2006;165:678-87. doi: 10.1667/RR3569.1. https://doi.org/10.1667/RR3569.1
  28. Ishikawa Y, Skowronski MT, Ishida H. Persistent increase in the amount of aquaporin-5 in the apical plasma membrane of rat parotid acinar cells induced by a muscarinic agonist SNI-2011. FEBS Lett 2000;477:253-7. doi: 10.1016/S0014-5793(00)01763-4. https://doi.org/10.1016/S0014-5793(00)01763-4
  29. Nusair S, Rubinow A. The use of oral pilocarpine in xerostomia and Sjogren's syndrome. Semin Arthritis Rheum 1999;28:360-7. doi: 10.1016/S0049-0172(99)80002-X. https://doi.org/10.1016/S0049-0172(99)80002-X