Journal of the Korea Academia-Industrial cooperation Society (한국산학기술학회논문지)

The Korea Academia-Industrial cooperation Society (한국산학기술학회)
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The effect of flavonoids on the TREK-1 channel

TREK-1 채널에 대한 플라보노이드의 효과

  • Kim, Yang-Mi (Dept. of Physiology, College of Medicine, Chungbuk National University) ;
  • Kim, Kyung-Ah (Dept. of Biomedical Engineering, College of Medicine, Chungbuk National University)
  • 김양미 (충북대학교 의과대학 생리학교실) ;
  • 김경아 (충북대학교 의과대학 의공학교실)
  • Received : 2011.04.27
  • Accepted : 2011.06.09
  • Published : 2011.06.30
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Abstract

TREK-1 channel is a member of the two-pore domain potassium (K2P) channel family that is regulated by intracellular pH, membrane stretch, polyunsaturated fatty acids, temperature, and some neuroprotectant agents. TREK-1 channel can influence neuronal excitability by regulating leakage of potassium ions and resting membrane potential. TREK-1 channel has been shown to be overexpressed in prostate cancer cells. Although the importance of these properties, relatively little is known about flavonoid effects in the regulations of TREK-1 channel. The purpose of the study was to screening of flavonoids as the TREK-1 channel modulator using one of electrophysiological techniques such as excised inside-out patch configuration. We demonstrated blocking effect on TREK-1 channel by flavonoids such as epigallocatechin-3-gallate (EGCG), curcumin and quercetin in CHO cells transiently expressing TREK-1 channel. The inhibition of TREK-1 channel by quercetin and curcumin was reversible, whereas EGCG was little reversible. Quercetin, EGCG and curcumin decreased the relative channel activity to 73%, 91% and 94%, respectively. The half-inhibitory concentration (IC50) of curcumin, quercetin and EGCG was $1.04{\pm}0.19\;{\mu}M$, $1.13{\pm}0.26\;{\mu}M$ and $13.5{\pm}2.20\;{\mu}M$ in CHO cells expressing TREK-1 channel, respectively. These results indicate that flavonoids might regulate TREK-1 and this regulation might be one of the pharmacological actions of flavonoid in nervous systems and cancer cells.

TREK-1 채널은 two-pore 도메인 포타슘 (K2P) 채널로서 세포내 pH, 세포막의 신전, 불 포화 지방산, 온도, 휘발성 마취제, 신경세포방어물질에 의해 잘 조절된다. TREK-1 채널은 포타슘 이동에 의해 신경세포의 흥분성과 안정막전압을 조절한다. 최근 TREK-1은 전립선 암세포에서도 과발현됨이 확인되었다. 이러한 중요성에도 불구하고, TREK-1 채널에 대한 플라보노이드 효과는 거의 알려지지 않았다. 본 연구의 목적은 전기생리학적 방법 중의 하나인 excised inside-out patch기법을 이용하여 TREK-1 채널을 조절하는 플라보노이드를 탐색하는 것이다. TREK-1 채널이 발현된 CHO 세포에서 단일채널 팻취고정 방법을 이용하여 커큐민 (curcumin), EGCG (epigallocatechin-3-gallate), 퀘르세틴 (quercetin)에 의한 TREK-1 채널의 차단효과를 증명하였다. 퀘르세틴과 커큐민의 차단효과는 가역적으로 회복되었으나 EGCG는 거의 회복되지 않았다. 퀘르세틴, EGCG, 커큐민의 상대적 채널 활성도 (relative channel activity)는 $73{\pm}2.3%$ (n=5), $91{\pm}3.2%$ (n=7), $94{\pm}5.6%$ (n=4)까지 감소하였다. CHO 세포에 발현된 TREK-1 채널에 대한 커큐민, 퀘르세틴, EGCG의 $IC_{50}$는 각각 $1.04{\pm}0.19\;{\mu}M$, $1.13{\pm}0.26\;{\mu}M$, $13.5{\pm}2.20\;{\mu}M$ 이었다. 이러한 결과는 플라보노이드가 TREK-1 채널을 억제하며, 이 조절은 신경계 또는 종양세포에서 플라보노이드의 약리학적 작용 중의 하나임을 제시한다.

Keywords

References

  1. E. Honore, "The neuronal background K2P channels: focus on TREK1", Nat Rev Neurosci, 8(4), pp. 251-261, April, 2007.
  2. C. Heurteaux, et al., "Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype", Nat Neurosci, 9(9), pp.1134-1141, September, 2006. https://doi.org/10.1038/nn1749
  3. C. Heurteaux, et al., "TREK-1, a $K^+$ channel involved in neuroprotection and general anesthesia", Embo J, 23(13), pp .2684-2695, July, 2004. https://doi.org/10.1038/sj.emboj.7600234
  4. Y. Maruyama, et al., "TREK-1: a potential target for novel antidepressants", Nihon Shinkei Seishin Yakurigaku Zasshi, 27(4), pp. 147-151, August, 2007
  5. I. Voloshyna, et al., "TREK-1 is a novel molecular target in prostate cancer", Cancer Res, 68(4), pp. 1197-1203, February, 2008. https://doi.org/10.1158/0008-5472.CAN-07-5163
  6. S. J. Tsai, "Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain $K^+$ channel TREK-1", Med Hypotheses, 70(3), pp. 548-550 August, 2008. https://doi.org/10.1016/j.mehy.2007.06.030
  7. H. J. Meadows, et al., "The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain $K^+$ channels TREK-1 and TRAAK", Brain Res, 892(1), pp. 94-101, February, 2001. https://doi.org/10.1016/S0006-8993(00)03239-X
  8. A. J. Patel, et al., "2P domain $K^+$ channels: novel pharmacological targets for volatile general anesthetics", Adv Exp Med Biol, 536, pp. 9-23. 2003. https://doi.org/10.1007/978-1-4419-9280-2_2
  9. F. Duprat, et al., "The neuroprotective agent riluzole activates the two P domain $K^+$ channels TREK-1 and TRAAK", Mol Pharmacol, 57(5), pp.906-912, May, 2000.
  10. E. J. Kim, et al., "Baicalein and wogonin are activators of rat TREK-2 two-pore domain $K^+$ channel", Acta Physiol (Oxf), pp. 1748-1716, February, 2011.
  11. J. A. Enyeart, et al., "Curcumin inhibits bTREK-1 $K^+$ channels and stimulates cortisol secretion from adrenocortical cells", Biochem Biophys Res Commun, 370(4), pp. 623-628, June, 2008. https://doi.org/10.1016/j.bbrc.2008.04.001
  12. C. Chen, et al., "Quercetin: a potential drug to reverse multidrug resistance", Life Sci, 87(11-12), pp. 333-338, September, 2010. https://doi.org/10.1016/j.lfs.2010.07.004
  13. A. Goel, et al., "Curcumin as "Curecumin": from kitchen to clinic", Biochem Pharmacol, 75(4), pp. 787-809, February, 2008. https://doi.org/10.1016/j.bcp.2007.08.016
  14. G. M. Cole, et al., "Neuroprotective effects of curcumin", Adv Exp Med Biol, 595, pp. 197-212. 2007. https://doi.org/10.1007/978-0-387-46401-5_8
  15. B. E. Bachmeier, et al., "Matrix metalloproteinases in cancer: comparison of known and novel aspects of their inhibition as a therapeutic approach", Expert Rev Anticancer Ther, 5(1), pp. 149-163, February, 2005. https://doi.org/10.1586/14737140.5.1.149
  16. M. M. Manson, et al., "Innovative agents in cancer prevention", Recent Results Cancer Res, 166, pp. 257-275. 2005. https://doi.org/10.1007/3-540-26980-0_17
  17. B. Illek, et al., "Flavonoids stimulate Cl conductance of human airway epithelium in vitro and in vivo", Am J Physiol, 275(5 Pt 1), pp. L902-910, November, 1998.
  18. D. H. Shin, et al., "Inhibition of Ca^{2+}-release-activated\;Ca^{2+} channel$ (CRAC) and $K^+$ channels by curcumin in Jurkat-T cells", J Pharmacol Sci, 115(2), pp. 144-154. 2011. https://doi.org/10.1254/jphs.10209FP
  19. S. Nishida, et al., "Possible Involvement of Ca Activated K Channels, SK Channel, in the Quercetin-Induced Vasodilatation", Korean J Physiol Pharmacol, 13(5), pp. 361-365, October, 2009. https://doi.org/10.4196/kjpp.2009.13.5.361
  20. L. Yang, et al., "Quercetin activates human Kv1.5 channels by a residue I502 in the S6 segment", Clin Exp Pharmacol Physiol, 36(2), pp. 154-161, February, 2009. https://doi.org/10.1111/j.1440-1681.2008.05061.x
  21. K. Kelemen, et al., "Green tea flavonoid epigallocatechin -3-gallate (EGCG) inhibits cardiac hERG potassium channels", Biochem Biophys Res Commun, 364(3), pp. 429-435, December, 2007. https://doi.org/10.1016/j.bbrc.2007.10.001
  22. H. Liu, et al., "Curcumin potently blocks Kv1.4 potassium channels", Biochem Biophys Res Commun, 344(4), pp. 1161-1165, June, 2006. https://doi.org/10.1016/j.bbrc.2006.04.020
  23. S. Saponara, et al., "Quercetin as a novel activator of L-type $Ca^{2+}$ channels in rat tail artery smooth muscle cells", Br J Pharmacol, 135(7), pp. 1819-1827, April, 2002. https://doi.org/10.1038/sj.bjp.0704631
  24. M. D. Brown, "Green tea (Camellia sinensis) extract and its possible role in the prevention of cancer", Altern Med Rev, 4(5), pp. 360-370, October, 1999.
  25. K. V. Hirpara, et al., "Quercetin and its derivatives: synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bio-availability", Anticancer Agents Med Chem, 9(2), pp. 138-161, February, 2009. https://doi.org/10.2174/187152009787313855
  26. C. K. Wong, et al., "House dust mite allergen Der p 1 elevates the release of inflammatory cytokines and expression of adhesion molecules in co-culture of human eosinophils and bronchial epithelial cells", Int Immunol, 18(8), pp. 1327-1335, August, 2006. https://doi.org/10.1093/intimm/dxl065
  27. R. Aalinkeel, et al., "The dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the expression of heat shock protein 90", Prostate, 68(16), pp. 1773-1789, December, 1.2008. https://doi.org/10.1002/pros.20845
  28. J. H. Lee, et al., "Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk", J Allergy Clin Immunol, 121(5), pp. 1225-1231, May, 2008. https://doi.org/10.1016/j.jaci.2007.12.1160
  29. E. J. Lee, et al., "Quercetin and kaempferol suppress immunoglobulin E-mediated allergic inflammation in RBL-2H3 and Caco-2 cells", Inflamm Res, 59(10), pp. 847-854, October, 2010. https://doi.org/10.1007/s00011-010-0196-2
  30. D. O. Moon, et al., "Curcumin attenuates ovalbumininduced airway inflammation by regulating nitric oxide", Biochem Biophys Res Commun, 375(2), pp. 275-279, October, 2008. https://doi.org/10.1016/j.bbrc.2008.08.025
  31. O. P. Hamill, et al., "Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches", Pflugers Arch, 391(2), pp.85-100, August, 1981. https://doi.org/10.1007/BF00656997
  32. F. Maingret, et al., "Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel", J Biol Chem, 274(38), pp. 26691-26696, September, 1999. https://doi.org/10.1074/jbc.274.38.26691
  33. A. Dedman, et al., "The mechano-gated K(2P) channel TREK-1", Eur Biophys J, 38(3), pp. 293-303, March, 2009. https://doi.org/10.1007/s00249-008-0318-8
  34. F. Maingret, et al., "TREK-1 is a heat-activated background $K^+$ channel", Embo J, 19(11), pp. 2483-2491, June, 2000. https://doi.org/10.1093/emboj/19.11.2483
  35. A. Cogolludo, et al., "The dietary flavonoid quercetin activates $BK_{Ca}$ currents in coronary arteries via production of $H_2O_2$. Role in vasodilatation", Cardiovasc Res, 73(2), pp. 424-431, January, 2007. https://doi.org/10.1016/j.cardiores.2006.09.008
  36. L. C. Pyle, et al., "Activation of CFTR by the Flavonoid Quercetin: Potential Use as a Biomarker of ${\Delta}F508$ CFTR Rescue", Am J Respir Cell Mol Biol, 43(5), pp. 607-616, December, 2009.
  37. H. Sun, et al., "Quercetin subunit specifically reduces GlyR-mediated current in rat hippocampal neurons", Neuroscience, 148(2), pp. 548-559, August, 2007. https://doi.org/10.1016/j.neuroscience.2007.06.007
  38. B. H. Lee, et al., "Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I", Mol Cells, 20(1), pp. 69-73, August, 2005.
  39. B. H. Lee, et al., "Quercetin Inhibits ${\alpha}3{\beta}4$ Nicotinic Acetylcholine Receptor-Mediated Ion Currents Expressed in Xenopus Oocytes", Korean J Physiol Pharmacol, 15(1), pp. 17-22, February, 2011. https://doi.org/10.4196/kjpp.2011.15.1.17
  40. E. H. Lee, et al., "Effects of quercetin on single $Ca^{2+}$ release channel behavior of skeletal muscle", Biophys J, 82(3), pp. 1266-1277, March, 2002. https://doi.org/10.1016/S0006-3495(02)75483-0
  41. B. H. Choi, et al., "Effects of (-)-epigallocatechin -3-gallate, the main component of green tea, on the cloned rat brain Kv1.5 potassium channels", Biochem Pharmacol, 62(5), pp. 527-535, September, 2001. https://doi.org/10.1016/S0006-2952(01)00678-5
  42. A. L. Berger, et al., "Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl^-$ channel activity", J Biol Chem, 280(7), pp. 5221-5226, February, 2005. https://doi.org/10.1074/jbc.M412972200

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