Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Differential effects of ginsenoside metabolites on slowly activating delayed rectifier K+ and KCNQ1 K+ channel currents

  • Choi, Sun-Hye (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) ;
  • Lee, Byung-Hwan (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) ;
  • Kim, Hyeon-Joong (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) ;
  • Jung, Seok-Won (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) ;
  • Hwang, Sung-Hee (Department of Pharmaceutical Engineering, Sangji University) ;
  • Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University)
  • Received : 2013.03.27
  • Accepted : 2013.05.27
  • Published : 2013.07.15
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Abstract

Channels formed by the co-assembly of the KCNQ1 subunit and the mink (KCNE1) subunit underline the slowly activating delayed rectifier $K^+$ channels ($I_{Ks}$) in the heart. This $K^+$ channel is one of the main pharmacological targets for the development of drugs against cardiovascular disease. Panax ginseng has been shown to exhibit beneficial cardiovascular effects. In a previous study, we showed that ginsenoside Rg3 activates human KCNQ1 $K^+$ channel currents through interactions with the K318 and V319 residues. However, little is known about the effects of ginsenoside metabolites on KCNQ1 $K^+$ alone or the KCNQ1 + KCNE1 $K^+$ ($I_{Ks}$) channels. In the present study, we examined the effect of protopanaxatriol (PPT) and compound K (CK) on KCNQ1 $K^+$ and $I_{Ks}$ channel activity expressed in Xenopus oocytes. PPT more strongly inhibited the $I_{Ks}$ channel currents than the currents of KCNQ1 $K^+$ alone in concentration- and voltage-dependent manners. The $IC_{50}$ values on $I_{Ks}$ and KCNQ1 alone currents for PPT were $5.18{\pm}0.13$ and $10.04{\pm}0.17{\mu}M$, respectively. PPT caused a leftward shift in the activation curve of $I_{Ks}$ channel activity, but minimally affected KCNQ1 alone. CK exhibited slight inhibition on $I_{Ks}$ and KCNQ1 alone $K^+$ channel currents. These results indicate that ginsenoside metabolites show limited effects on $I_{Ks}$ channel activity, depending on the structure of the ginsenoside metabolites.

Keywords

References

  1. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996;12:17-23. https://doi.org/10.1038/ng0196-17
  2. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1996;384:78-80. https://doi.org/10.1038/384078a0
  3. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996;384:80-83. https://doi.org/10.1038/384080a0
  4. Pusch M, Magrassi R, Wollnik B, Conti F. Activation and inactivation of homomeric KvLQT1 potassium channels. Biophys J 1998;75:785-792. https://doi.org/10.1016/S0006-3495(98)77568-X
  5. Seebohm G, Scherer CR, Busch AE, Lerche C. Identification of specific pore residues mediating KCNQ1 inactivation. A novel mechanism for long QT syndrome. J Biol Chem 2001;276:13600-13605. https://doi.org/10.1074/jbc.M008373200
  6. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997;15:186-189. https://doi.org/10.1038/ng0297-186
  7. Mall M, Bleich M, Schurlein M, Kuhr J, Seydewitz HH, Brandis M, Greger R, Kunzelmann K. Cholinergic ion secretion in human colon requires coactivation by cAMP. Am J Physiol 1998;275(6 Pt 1):G1274- G1281.
  8. Grahammer F, Herling AW, Lang HJ, Schmitt-Graff A, Wittekindt OH, Nitschke R, Bleich M, Barhanin J, Warth R. The cardiac $K^{+}$ channel KCNQ1 is essential for gastric acid secretion. Gastroenterology 2001;120:1363-1371. https://doi.org/10.1053/gast.2001.24053
  9. Snyders DJ. Structure and function of cardiac potassium channels. Cardiovasc Res 1999;42:377-390. https://doi.org/10.1016/S0008-6363(99)00071-1
  10. Cheng JH, Kodama I. Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin 2004;25:137-145.
  11. Sanguinetti MC. Dysfunction of delayed rectifier potassium channels in an inherited cardiac arrhythmia. Ann N Y Acad Sci 1999;868:406-413. https://doi.org/10.1111/j.1749-6632.1999.tb11302.x
  12. Roden DM, Balser JR, George AL Jr, Anderson ME. Cardiac ion channels. Annu Rev Physiol 2002;64:431-475. https://doi.org/10.1146/annurev.physiol.64.083101.145105
  13. Tristani-Firouzi M, Sanguinetti MC. Structural determinants and biophysical properties of HERG and KCNQ1 channel gating. J Mol Cell Cardiol 2003;35:27-35. https://doi.org/10.1016/S0022-2828(02)00286-9
  14. Robbins J. KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Pharmacol Ther 2001;90:1-19. https://doi.org/10.1016/S0163-7258(01)00116-4
  15. Nah SY. Ginseng: recent advances and trends. Korea J Ginseng Sci 1997;21:1-12.
  16. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-1693. https://doi.org/10.1016/S0006-2952(99)00212-9
  17. Chen X, Gillis CN, Moalli R. Vascular effects of ginsenosides in vitro. Br J Pharmacol 1984;82:485-491. https://doi.org/10.1111/j.1476-5381.1984.tb10784.x
  18. Chen X. Cardiovascular protection by ginsenosides and their nitric oxide releasing action. Clin Exp Pharmacol Physiol 1996;23:728-732. https://doi.org/10.1111/j.1440-1681.1996.tb01767.x
  19. Bai CX, Sunami A, Namiki T, Sawanobori T, Furukawa T. Electrophysiological effects of ginseng and ginsenoside Re in guinea pig ventricular myocytes. Eur J Pharmacol 2003;476:35-44. https://doi.org/10.1016/S0014-2999(03)02174-5
  20. Furukawa T, Bai CX, Kaihara A, Ozaki E, Kawano T, Nakaya Y, Awais M, Sato M, Umezawa Y, Kurokawa J. Ginsenoside Re, a main phytosterol of Panax ginseng, activates cardiac potassium channels via a nongenomic pathway of sex hormones. Mol Pharmacol 2006;70:1916-1924. https://doi.org/10.1124/mol.106.028134
  21. Choi SH, Shin TJ, Lee BH, Chu DH, Choe H, Pyo MK, Hwang SH, Kim BR, Lee SM, Lee JH et al. Ginsenoside Rg3 activates human KCNQ1 $K^{+}$ channel currents through interacting with the K318 and V319 residues: a role of KCNE1 subunit. Eur J Pharmacol 2010;637:138-147. https://doi.org/10.1016/j.ejphar.2010.04.001
  22. Choi SH, Shin TJ, Hwang SH, Lee BH, Kang J, Kim HC, Oh JW, Bae CS, Lee SH, Nah SY. Differential effects of ginsenoside metabolites on HERG $K^{+}$ channel currents. J Ginseng Res 2011;35:191-199. https://doi.org/10.5142/jgr.2011.35.2.191
  23. Hasegawa H, Suzuki R, Nagaoka T, Tezuka Y, Kadota S, Saiki I. Prevention of growth and metastasis of murine melanoma through enhanced natural-killer cytotoxicity by fatty acid-conjugate of protopanaxatriol. Biol Pharm Bull 2002;25:861-866. https://doi.org/10.1248/bpb.25.861
  24. Akao T, Kanaoka M, Kobashi K. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration: measurement of compound K by enzyme immunoassay. Biol Pharm Bull 1998;21:245-249. https://doi.org/10.1248/bpb.21.245
  25. Bae EA, Park SY, Kim DH. Constitutive beta-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol Pharm Bull 2000;23:1481-1485. https://doi.org/10.1248/bpb.23.1481
  26. Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003;31:1065-1071. https://doi.org/10.1124/dmd.31.8.1065
  27. Lee JH, Jeong SM, Kim JH, Lee BH, Yoon IS, Lee JH, Choi SH, Kim DH, Rhim H, Kim SS et al. Characteristics of ginsenoside Rg3-mediated brain $Na^{+}$ current inhibition. Mol Pharmacol 2005;68:1114-1126. https://doi.org/10.1124/mol.105.015115
  28. Wakabayashi C, Hasegawa H, Murata J, Saiki I. In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration. Oncol Res 1997;9:411-417.
  29. Wang CZ, Du GJ, Zhang Z, Wen XD, Calway T, Zhen Z, Musch MW, Bissonnette M, Chang EB, Yuan CS. Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer. Int J Oncol 2012;40:1970-1976.
  30. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997;17:338-340. https://doi.org/10.1038/ng1197-338
  31. Seebohm G, Pusch M, Chen J, Sanguinetti MC. Pharmacological activation of normal and arrhythmia-associated mutant KCNQ1 potassium channels. Circ Res 2003;93:941-947. https://doi.org/10.1161/01.RES.0000102866.67863.2B
  32. Salata JJ, Jurkiewicz NK, Wang J, Evans BE, Orme HT, Sanguinetti MC. A novel benzodiazepine that activates cardiac slow delayed rectifier $K^{+}$ currents. Mol Pharmacol 1998;54:220-230. https://doi.org/10.1124/mol.54.1.220
  33. Lee JH, Jeong SM, Kim JH, Lee BH, Yoon IS, Lee JH, Choi SH, Lee SM, Park YS, Lee JH et al. Effects of ginsenosides and their metabolites on voltage-dependent Ca(2+) channel subtypes. Mol Cells 2006;21:52-62.
  34. Kim JH, Hong YH, Lee JH, Kim DH, Nam G, Jeong SM, Lee BH, Lee SM, Nah SY. A role for the carbohydrate portion of ginsenoside Rg3 in $Na^{+}$ channel inhibition. Mol Cells 2005;19:137-142.
  35. Shin TJ, Hwang SH, Choi SH, Lee BH, Kang J, Kim HJ, Zukin RS, Rhim H, Nah SY. Effects of protopanaxatriol-ginsenoside metabolites on rat N-methyl-d-aspartic acid receptor-mediated ion currents. Korean J Physiol Pharmacol 2012;16:113-118. https://doi.org/10.4196/kjpp.2012.16.2.113