The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

DA-6034 Induces $[Ca^{2+}]_i$ Increase in Epithelial Cells

  • Yang, Yu-Mi (Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry) ;
  • Park, Soonhong (Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry) ;
  • Ji, HyeWon (Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry) ;
  • Kim, Tae-Im (Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine) ;
  • Kim, Eung Kweon (Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine) ;
  • Kang, Kyung Koo (Research Institutes, Dong-A Pharmaceutical Company) ;
  • Shin, Dong Min (Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry)
  • Received : 2013.07.16
  • Accepted : 2013.12.22
  • Published : 2014.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

DA-6034, a eupatilin derivative of flavonoid, has shown potent effects on the protection of gastric mucosa and induced the increases in fluid and glycoprotein secretion in human and rat corneal and conjunctival cells, suggesting that it might be considered as a drug for the treatment of dry eye. However, whether DA-6034 induces $Ca^{2+}$ signaling and its underlying mechanism in epithelial cells are not known. In the present study, we investigated the mechanism for actions of DA-6034 in $Ca^{2+}$ signaling pathways of the epithelial cells (conjunctival and corneal cells) from human donor eyes and mouse salivary gland epithelial cells. DA-6034 activated $Ca^{2+}$-activated $Cl^-$ channels (CaCCs) and increased intracellular calcium concentrations ($[Ca^{2+}]_i$) in primary cultured human conjunctival cells. DA-6034 also increased $[Ca^{2+}]_i$ in mouse salivary gland cells and human corneal epithelial cells. $[Ca^{2+}]_i$ increase of DA-6034 was dependent on the $Ca^{2+}$ entry from extracellular and $Ca^{2+}$ release from internal $Ca^{2+}$ stores. Interestingly, these effects of DA-6034 were related to ryanodine receptors (RyRs) but not phospholipase C/inositol 1,4,5-triphosphate ($IP_3$) pathway and lysosomal $Ca^{2+}$ stores. These results suggest that DA-6034 induces $Ca^{2+}$ signaling via extracellular $Ca^{2+}$ entry and RyRs-sensitive $Ca^{2+}$ release from internal $Ca^{2+}$ stores in epithelial cells.

Keywords

References

  1. Petersen OH, Tepikin AV. Polarized calcium signaling in exocrine gland cells. Annu Rev Physiol. 2008;70:273-299. https://doi.org/10.1146/annurev.physiol.70.113006.100618
  2. Melvin JE, Yule D, Shuttleworth T, Begenisich T. Regulation of fluid and electrolyte secretion in salivary gland acinar cells. Annu Rev Physiol. 2005;67:445-469. https://doi.org/10.1146/annurev.physiol.67.041703.084745
  3. Aluru SV, Agarwal S, Srinivasan B, Iyer GK, Rajappa SM, Tatu U, Padmanabhan P, Subramanian N, Narayanasamy A. Lacrimal proline rich 4 (LPRR4) protein in the tear fluid is a potential biomarker of dry eye syndrome. PLoS One. 2012;7:e51979. https://doi.org/10.1371/journal.pone.0051979
  4. Cheng EY, Goss CH, McKone EF, Galic V, Debley CK, Tonelli MR, Aitken ML. Aggressive prenatal care results in successful fetal outcomes in CF women. J Cyst Fibros. 2006;5:85-91. https://doi.org/10.1016/j.jcf.2006.01.002
  5. Ferrándiz ML, Alcaraz MJ. Anti-inflammatory activity and inhibition of arachidonic acid metabolism by flavonoids. Agents Actions. 1991;32:283-288. https://doi.org/10.1007/BF01980887
  6. Li BQ, Fu T, Gong WH, Dunlop N, Kung H, Yan Y, Kang J, Wang JM. The flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines. Immunopharmacology. 2000;49:295-306. https://doi.org/10.1016/S0162-3109(00)00244-7
  7. Sadik CD, Sies H, Schewe T. Inhibition of 15-lipoxygenases by flavonoids: structure-activity relations and mode of action. Biochem Pharmacol. 2003;65:773-781. https://doi.org/10.1016/S0006-2952(02)01621-0
  8. Choi SM, Shin JH, Kang KK, Ahn BO, Yoo M. Gastroprotective effects of DA-6034, a new flavonoid derivative, in various gastric mucosal damage models. Dig Dis Sci. 2007;52:3075-3080. https://doi.org/10.1007/s10620-006-9657-4
  9. Kim YS, Son M, Ko JI, Cho H, Yoo M, Kim WB, Song IS, Kim CY. Effect of DA-6034, a derivative of flavonoid, on experimental animal models of inflammatory bowel disease. Arch Pharm Res. 1999;22:354-360. https://doi.org/10.1007/BF02979057
  10. Kim EJ, Chung MY, Chung HJ, Son MW, Kwon JW, Yoo M, Lee MG. Pharmacokinetics of 7-carboxymethyloxy-3',4',5- trimethoxy flavone (DA-6034), a derivative of flavonoid, in mouse and rat models of chemically-induced inflammatory bowel disease. J Pharm Pharmacol. 2006;58:27-35. https://doi.org/10.1211/jpp.58.1.0004
  11. Ko SH, Yoo DY, Kim YJ, Choi SM, Kang KK, Kim H, Kim N, Kim JS, Kim JM. A mechanism for the action of the compound DA-6034 on NF-${\kappa}B$ pathway activation in Helicobacter pyloriinfected gastric epithelial cells. Scand J Immunol. 2011;74: 253-263. https://doi.org/10.1111/j.1365-3083.2011.02577.x
  12. Lee JS, Kim HS, Hahm KB, Sohn MW, Yoo M, Johnson JA, Surh YJ. Inhibitory effects of 7-carboxymethyloxy-3',4',5- trimethoxyflavone (DA-6034) on Helicobacter pylori-induced NF-kappa B activation and iNOS expression in AGS cells. Ann N Y Acad Sci. 2007;1095:527-535. https://doi.org/10.1196/annals.1397.057
  13. Choi SM, Lee YG, Seo MJ, Kang KK, Ahn BO, Yoo M. Effects of DA-6034 on aqueous tear fluid secretion and conjunctival goblet cell proliferation. J Ocul Pharmacol Ther. 2009;25:209-214. https://doi.org/10.1089/jop.2008.0126
  14. Choi SM, Seo MJ, Lee YG, Lee MJ, Jeon HJ, Kang KK, Ahn BO, Yoo M. Effects of DA-6034, a flavonoid derivative, on mucin-like glycoprotein and ocular surface integrity in a rabbit model. Arzneimittelforschung. 2009;59:498-503.
  15. Seo MJ, Kim JM, Lee MJ, Sohn YS, Kang KK, Yoo M. The therapeutic effect of DA-6034 on ocular inflammation via suppression of MMP-9 and inflammatory cytokines and activation of the MAPK signaling pathway in an experimental dry eye model. Curr Eye Res. 2010;35:165-175. https://doi.org/10.3109/02713680903453494
  16. Jo H, Byun HM, Lee SI, Shin DM. Initiation site of Ca2+ entry evoked by endoplasmic reticulum Ca2+ depletion in mouse parotid and pancreatic acinar cells. Yonsei Med J. 2007;48:526-530. https://doi.org/10.3349/ymj.2007.48.3.526
  17. Yang YM, Jung HH, Lee SJ, Choi HJ, Kim MS, Shin DM. TRPM7 Is Essential for RANKL-Induced Osteoclastogenesis. Korean J Physiol Pharmacol. 2013;17:65-71. https://doi.org/10.4196/kjpp.2013.17.1.65
  18. Zeng W, Lee MG, Yan M, Diaz J, Benjamin I, Marino CR, Kopito R, Freedman S, Cotton C, Muallem S, Thomas P. Immuno and functional characterization of CFTR in submandibular and pancreatic acinar and duct cells. Am J Physiol. 1997;273:C442-455. https://doi.org/10.1152/ajpcell.1997.273.2.C442
  19. Park S, Lee SI, Shin DM. Role of regulators of g-protein signaling 4 in Ca2+ signaling in mouse pancreatic acinar cells. Korean J Physiol Pharmacol. 2011;15:383-388. https://doi.org/10.4196/kjpp.2011.15.6.383
  20. Vermassen E, Parys JB, Mauger JP. Subcellular distribution of the inositol 1,4,5-trisphosphate receptors: functional relevance and molecular determinants. Biol Cell. 2004;96:3-17. https://doi.org/10.1016/j.biolcel.2003.11.004
  21. Frizzell RA, Hanrahan JW. Physiology of epithelial chloride and fluid secretion. Cold Spring Harb Perspect Med. 2012;2:a009563.
  22. Haddad JJ. Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF-kappaB nuclear translocation and activation. Biochem Biophys Res Commun. 2002;296:847-856. https://doi.org/10.1016/S0006-291X(02)00947-6
  23. Rottner M, Freyssinet JM, Martínez MC. Mechanisms of the noxious inflammatory cycle in cystic fibrosis. Respir Res. 2009;10:23. https://doi.org/10.1186/1465-9921-10-23
  24. Yamamori E, Iwasaki Y, Oki Y, Yoshida M, Asai M, Kambayashii M, Oiso Y, Nakashima N. Possible involvement of ryanodine receptor-mediated intracellular calcium release in the effect of corticotropin-releasing factor on adrenocorticotropin secretion. Endocrinology. 2004;145:36-38. https://doi.org/10.1210/en.2003-1222
  25. Lin F, Xin Y, Wang J, Ma L, Liu J, Liu C, Long L, Wang F, Jin Y, Zhou J, Chen J. Puerarin facilitates Ca2+-induced Ca2+ release triggered by KCl-depolarization in primary cultured rat hippocampal neurons. Eur J Pharmacol. 2007;570:43-49. https://doi.org/10.1016/j.ejphar.2007.05.023
  26. Hartzell C, Putzier I, Arreola J. Calcium-activated chloride channels. Annu Rev Physiol. 2005;67:719-758. https://doi.org/10.1146/annurev.physiol.67.032003.154341

Cited by

  1. Helicobacter pylori γ-glutamyl transpeptidase-induced Ca2+ release via PLC-IP3 receptors in AGS cells vol.60, pp.12, 2014, https://doi.org/10.1139/cjm-2014-0464
  2. Hydrogen sulfide: a novel gaseous signaling molecule and intracellular Ca2+ regulator in rat parotid acinar cells vol.309, pp.7, 2015, https://doi.org/10.1152/ajpcell.00147.2015