Ginseng Saponin as an Antagonist for Gap Junctional Channels

  • Rhee, Seung-Keun (Department of Biochemistry, College of Science, Yeungnam University)
  • Published : 2006.06.01


Gap junctional channels, allowing rapid intercellular communication and synchronization of coupled cell activities, play crucial roles in many signaling processes, including a variety of cell activities. Consequently, a modulation of the gap junctional intercellular communication (GJIC) should be a potential pharmacological target. In the present, the GJIC of a epithelial-derived rat mammary cells (BICR-M1Rk) was assessed in the presence of ginseng saponin, by using an established method of scrape-loading dye transfer assay. The transfer of Lucifer yellow (diameter: 1.2 nm) among the neighboring BICR-M1Rk cells, in which connexin43 (Cx43) is a major gap junction channel-forming protein, was significantly retarded at a concentration of $10{\mu}g/ml$ ginseng saponin. By using both methods of RT-PCR and Western blotting, it was demonstrated that ginseng saponin modulated neither the mRNA synthesis of Cx43 nor the translational process of Cx43. This ginseng saponin-induced modification of GJIC was a similar phenomenon observed under the $\beta$-glycyrrhetinic acid treatment, a well-known gap junction channel blocker. Taken together, it is reasonable to conclude that the ginseng saponin inhibits GJIC only by modulating the gating property of gap junction channels.



  1. Bennett, M. V. L., Barrio, L. C., Bargiello, T. A. and Spray, D. C. : Gap junctions: new tools, new answers, new questions. Neuron. 6, 305-320 (1991)
  2. Kumar, N. and Gilula, N. B. : The gap junction communication channel. Cell. 84, 381-388 (1996)
  3. Musil, L. S. and Goodenough, D. A. : Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from ER. Cell. 74, 1065-1077 (1993)
  4. Lampe, P. D. : Analyzing phobol ester effects on gap junction communication: a dramatic inhibition of assembly. J. Cell Biol. 127, 1895-1905 (1994)
  5. Falk, M., Buehler, L. K., Kumar, N. and Gilula, N. B. : Cellfree synthesis and assembly of connexins into functional gap junction membrane channels. EMBO J. 16, 2703-2716 (1997)
  6. Attele, A. S., Wu, J. A. and Yuan, C. S. : Ginseng pharmacology: multiple constituents and multiple actions. Biochem. Pharmacol. 58, 1685-1693 (1999)
  7. Rudakewich, M., Ba, F. and Benishin, C. G. : Neurotrophic and neuroprotective actions of ginsenosides Rb(1) and Rg(1). Planta Med. 67, 533-537 (2001)
  8. Choi, S. : Epidermis proliferate effect of the Panax ginseng ginsenoside Rb2. Arch. Pharm. Res. 25, 71-76 (2002)
  9. Shen, L. H. and Zhang, J. T. : Ginsenoside Rg1 promotes proliferation of hippocampal progenitor cells. Neurol. Res. 26, 422-428 (2004)
  10. Tatsuka, M., Maeda, M. and Ota, T. : Anticarcinogenic eddect and enhancement of metastatic potential of BALB/c 3T3 cells by ginsenoside Rh(2). Jpn. J. Cancer Res. 92, 1184-1189 (2001)
  11. Kim, N. D., Kim, E. M., Kang, K. W., Cho, M. K., Choi, S. Y. and Kim, S. G. : Ginsenoside Rg3 inhibits phenylephrineinduced vasicular contraction through induction of nitric oxide synthase. Br. J. Pharmacol. 140, 661-670 (2003)
  12. Liu, D., Li, B., Liu, Y., Attele, A. S., Kyle, J. W. and Yuan, C. S.: Voltage-dependent inhibition of brain Z$Na^+$ channels by American ginseng. Eur. J. Pharmacol. 413, 47-54 (2001)
  13. Lee, J. H., Jeong, S. M., Lee, B. H., Kim, J. H., Ko, S. R., Kim, S. H., Lee, S. M. and Nah, S. Y. : Effect of calmodulin on ginseng saponin-induced Ca2+-activated Cl--channel activation in Xenopus laevis oocytes. Arch. Pharm. Res. 28, 413-420 (2005)
  14. Xu, Y. X., Shi, J. S. and Jiang, Z. L. : Inhibitory influence of ginsenoside Rb(3) on activation of strychnine-sensitive glycine receptors in hippocampal neurons of rat. Brain Res. 1037, 99-106 (2005)
  15. Sala, F., Mulet, J., Choi, S., Jung, S. Y., Nah, S. Y., Rhim, H., Valor, L. M., Criado, M. and Sala, S. : Effects of ginsenoside Rg2 on human neuronal nicotinic acetylcholine receptors. J. Pharmacol. Exp. Ther. 301, 1052-1059 (2002)
  16. Quist, A. P., Rhee, S. K., Lin, H. and Lal, R. : Physiological role of gap-junctional hemichannels: Extracellular calciumdependent isosmotic volume regulation. J. Cell Biol. 148, 1063-1074 (2000)
  17. Lee, S. W., Tomasetto, C., Paul, D., Keyomarsi, K. and Sager, R. : Transcriptional down-regulation of gap junction proteins blocks junctional communication in human mammary tumor cell-lines. J. Cell Biol. 118, 1213-1221 (1992)
  18. Fernandes, R., Girao, H. and Pereira, P. : High glucose downregulates intercellular communication in retinal endothelial cells by enhancing degradation of connexin 43 by a proteasome-dependent mechanism. J. Biol. Chem. 279, 27219-27224 (2004)
  19. Omori, Y., Duflot-Dancer, A., Mesnil., M. and Yamasaki, H. : Role of connexin genes in cell growth control: approach with site-directed mutagenesis and dominant-negative effects. Toxicol. Lett. 96, 105-110 (1998)
  20. Rhee, S. K., Bevans, C. G. and Harris, A. L. : Channel-forming activity of immunoaffinity-purified connexin32 in single phospholipid membranes. Biochemistry. 35, 9212-9223 (1996)
  21. Yamamoto, Y., Fukuta, H., Nakahira, Y. and Suzuki, H. : Blockade by 18 ${\beta}-glycyrrhetinic$ acid of intercellular electrical coupling in guinea-pig arterioles. J. Physiol. 511, 501-508 (1998)
  22. Hong, E. J., Huh, K. and Rhee, S. K. : Effect of ginseng saponin on gap junction channel reconstituted with connexin32. Arch. Pharm. Res. 19, 264-268 (1996)
  23. Choi, S., Rho, S. H., Jung, S. Y., Kim, S. C., Park, C. S. and Nah, S. Y. : A novel activation of $Ca^{2+}-activated\;Cl^-$ channel in Xenopus oocytes by ginseng saponins: evidence for the involvement of phospholipase C and intracellular $Ca^{2+}$ mobilization. Br. J. Pharmacol. 132, 641-648 (2001)
  24. Tachikawa, E., Kudo, K., Kashimoto, T. and Takahashi, E. J. : Ginseng saponins recude acetylcholine-evoked $Na^+$ influx and catecholamine secretion in bovine adrenal chromaffin cells. J. Pharmacol. Exp. Ther. 279, 629-636 (1995)
  25. Nah, S. Y., Park, H. J. and McCleskey, E. W. : A trace component of ginseng that inhibits $Cx^{2+}$ channels through a pertusssis toxin-sensitive G protein. Proc. Natl. Acad. Sci. USA 92, 8739-8743 (1995)
  26. Zhang, C., Yu, H., Bao, Y., An, L. and Jin, F. : Purification and characterization of $ginsenosid-{\beta}-glucosidase$ from Ginseng. Chem. Pharm. Bull. 49, 795-598 (2001)
  27. Fujikata-Yamamoto, K., Ota, T., Odashima, S., Abe, H. and Arichi, S. : Different responses in the cell cycle of tumor cells to Ginsenoside $Rb_2$. Cancer J. 1, 349-352 (1987)
  28. Lee, K. Y., Park, J. A., Chung, E., Lee, Y. H., Kim, S. I. and Lee, S. K. : Ginsenoside-$Rb_2$ blocks the cell cycle of SKKEP-1 cells at the $G_1$/S boundary by selectively inducing the protein expression of p27. Cancer Lett. 110, 193-200 (1996)
  29. Panwar, M., Samarth, R., Kumar, M., Yoon, W. J. and Kumar, A. : Inhibition of benzo(a)pyrene induced lung adenoma by panax ginseng extract, EFLA400, in Swiss albino mice. Biol Pharm Bull. 28(11), 2063-2067 (2005)