Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Differential Effects of Quercetin and Quercetin Glycosides on Human α7 Nicotinic Acetylcholine Receptor-Mediated Ion Currents

  • Lee, Byung-Hwan (Department of Physiology, College of Veterinary Medicine and BioMolecular Informatics Center, Konkuk University) ;
  • Choi, Sun-Hye (Department of Physiology, College of Veterinary Medicine and BioMolecular Informatics Center, Konkuk University) ;
  • Kim, Hyeon-Joong (Department of Physiology, College of Veterinary Medicine and BioMolecular Informatics Center, Konkuk University) ;
  • Jung, Seok-Won (Department of Physiology, College of Veterinary Medicine and BioMolecular Informatics Center, Konkuk University) ;
  • Hwang, Sung-Hee (Department of Pharmaceutical Engineering, Sangji University) ;
  • Pyo, Mi-Kyung (International Ginseng and Herb Research Institute) ;
  • Rhim, Hyewhon (Life Science Division, Korea Institute of Science and Technology) ;
  • Kim, Hyoung-Chun (Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University) ;
  • Kim, Ho-Kyoung (Mibyeong Research Center, Korea Institute of Oriental Medicine) ;
  • Lee, Sang-Mok (Department of Physiology, College of Veterinary Medicine and BioMolecular Informatics Center, Konkuk University) ;
  • Nah, Seung-Yeol (Department of Physiology, College of Veterinary Medicine and BioMolecular Informatics Center, Konkuk University)
  • Received : 2015.09.21
  • Accepted : 2016.01.22
  • Published : 2016.07.01
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Abstract

Quercetin is a flavonoid usually found in fruits and vegetables. Aside from its antioxidative effects, quercetin, like other flavonoids, has a various neuropharmacological actions. Quercetin-3-O-rhamnoside (Rham1), quercetin-3-O-rutinoside (Rutin), and quercetin-3-(2(G)-rhamnosylrutinoside (Rham2) are mono-, di-, and tri-glycosylated forms of quercetin, respectively. In a previous study, we showed that quercetin can enhance ${\alpha}7$ nicotinic acetylcholine receptor (${\alpha}7$ nAChR)-mediated ion currents. However, the role of the carbohydrates attached to quercetin in the regulation of ${\alpha}7$ nAChR channel activity has not been determined. In the present study, we investigated the effects of quercetin glycosides on the acetylcholine induced peak inward current ($I_{ACh}$) in Xenopus oocytes expressing the ${\alpha}7$ nAChR. $I_{ACh}$ was measured with a two-electrode voltage clamp technique. In oocytes injected with ${\alpha}7$ nAChR copy RNA, quercetin enhanced $I_{ACh}$, whereas quercetin glycosides inhibited $I_{ACh}$. Quercetin glycosides mediated an inhibition of $I_{ACh}$, which increased when they were pre-applied and the inhibitory effects were concentration dependent. The order of $I_{ACh}$ inhibition by quercetin glycosides was Rutin${\geq}$Rham1>Rham2. Quercetin glycosides-mediated $I_{ACh}$ enhancement was not affected by ACh concentration and appeared voltage-independent. Furthermore, quercetin-mediated $I_{ACh}$ inhibition can be attenuated when quercetin is co-applied with Rham1 and Rutin, indicating that quercetin glycosides could interfere with quercetin-mediated ${\alpha}7$ nAChR regulation and that the number of carbohydrates in the quercetin glycoside plays a key role in the interruption of quercetin action. These results show that quercetin and quercetin glycosides regulate the ${\alpha}7$ nAChR in a differential manner.

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References

  1. Azevedo, M. I., Pereira, A. F., Nogueira, R. B., Rolim, F. E., Brito, G. A., Wong, D. V., Lima-Junior, R. C., de Albuquerque Ribeiro, R. and Vale, M. L. (2013) The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Mol. Pain 9, 53. https://doi.org/10.1186/1744-8069-9-53
  2. Boulter, J., Connolly, J., Deneris, E., Goldman, D., Heinemann, S. and Patrick, J. (1987) Functional expression of two neuronal nicotinic acetylcholine receptors from cDNA clones identifies a gene family. Proc. Natl. Acad. Sci. U.S.A. 84, 7763-7767. https://doi.org/10.1073/pnas.84.21.7763
  3. Castro, N. G. and Albuquerque, E. X. (1995) Alpha-bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability. Biophys. J. 68, 516-524. https://doi.org/10.1016/S0006-3495(95)80213-4
  4. Changeux, J. and Edelstein, S. J. (2001) Allosteric mechanisms in normal and pathological nicotinic acetylcholine receptors. Curr. Opin. Neurobiol. 11, 369-377. https://doi.org/10.1016/S0959-4388(00)00221-X
  5. Chavez-Noriega, L. E., Crona, J. H., Washburn, M. S., Urrutia, A., Elliott, K. J. and Johnson, E. C. (1997) Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors $h{\alpha}2{\beta}2$, $h{\alpha}2{\beta}4$, $h{\alpha}3{\beta}2$, $h{\alpha}3{\beta}4$, $h{\alpha}4{\beta}2$, $h{\alpha}4{\beta}4$ and $h{\alpha}7$ expressed in Xenopus oocytes. J. Pharmacol. Exp. Ther. 280, 346-356.
  6. Chini, B., Raimond, E., Elgoyhen, A. B., Moralli, D., Balzaretti, M. and Heinemann, S. (1994) Molecular cloning and chromosomal localization of the human alpha 7-nicotinic receptor subunit gene (CHRNA7). Genomics 19, 379-381. https://doi.org/10.1006/geno.1994.1075
  7. Couturier, S., Bertrand, D., Matter, J. M., Hernandez, M. C., Bertrand, S., Millar, N., Valera, S., Barkas, T. and Ballivet, M. (1990) A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is developmentally regulated and forms a homo-oligomeric channel blocked by alpha-BTX. Neuron 5, 847-856 https://doi.org/10.1016/0896-6273(90)90344-F
  8. Dani, J. A. and Bertrand, D. (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu. Rev. Pharmacol. Toxicol. 47, 699-729. https://doi.org/10.1146/annurev.pharmtox.47.120505.105214
  9. Dascal, N. (1987) The use of Xenopus oocytes for the study of ion channels. CRC Crit. Rev. Biochem. 22, 317-387. https://doi.org/10.3109/10409238709086960
  10. Elgoyhen, A. B., Johnson, D. S., Boulter, J., Vetter, D. E. and Heinemann, S. (1994) ${\alpha}9$: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79, 705-715 https://doi.org/10.1016/0092-8674(94)90555-X
  11. Galzi, J. L., Devillers-Thiery, A., Hussy, N., Bertrand, S., Changeux, J. P. and Bertrand, D. (1992) Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Nature 359, 500-505. https://doi.org/10.1038/359500a0
  12. Gilbert, D., Lecchi, M., Arnaudeau, S., Bertrand, D. and Demaurex, N. (2009) Local and global calcium signals associated with the opening of neuronal alpha7 nicotinic acetylcholine receptors. Cell Calcium 45, 198-207. https://doi.org/10.1016/j.ceca.2008.10.003
  13. Gotti, C., Carbonnelle, E., Moretti, M., Zwart, R. and Clementi, F. (2000) Drugs selective for nicotinic receptor subtypes: a real possibility or a dream? Behav. Brain Res. 113, 183-192. https://doi.org/10.1016/S0166-4328(00)00212-6
  14. Gotti, C. and Clementi, F. (2004) Neuronal nicotinic receptors: from structure to pathology. Prog. Neurobiol. 74, 363-396. https://doi.org/10.1016/j.pneurobio.2004.09.006
  15. Griebel, G., Perrault, G., Tan, S., Schoemaker, H. and Sanger, D. J. (1999) Pharmacological studies on synthetic flavonoids: comparison with diazepam. Neuropharmacology 38, 965-977. https://doi.org/10.1016/S0028-3908(99)00026-X
  16. Harborne, J. B. and Williams, C. A. (2000) Advances in flavonoid research since 1992. Phytochemistry 55, 481-504. https://doi.org/10.1016/S0031-9422(00)00235-1
  17. Havsteen, B. H. (2002) The biochemistry and medical significance of the flavonoids. Pharmacol. Ther. 96, 67-202. https://doi.org/10.1016/S0163-7258(02)00298-X
  18. Jensen, M. L., Schousboe, A. and Ahring, P. K. (2005) Charge selectivity of the Cys-loop family of ligand-gated ion channels. J. Neurochem. 92, 217-225. https://doi.org/10.1111/j.1471-4159.2004.02883.x
  19. Kandaswami, C. and Middleton, E., Jr. (1994) Free radical scavenging and antioxidant activity of plant flavonoids. Adv. Exp. Med. Biol. 366, 351-376. https://doi.org/10.1007/978-1-4615-1833-4_25
  20. Karlin, A. (2002) Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev. Neurosci. 3, 102-114. https://doi.org/10.1038/nrn731
  21. Khiroug, L., Giniatullin, R., Klein, R. C., Fayuk, D. and Yakel, J. L. (2003) Functional mapping and $Ca^{2+}$ regulation of nicotinic acetylcholine receptor channels in rat hippocampal CA1 neurons. J. Neurosci. 23, 9024-9031. https://doi.org/10.1523/JNEUROSCI.23-27-09024.2003
  22. Kim, H. J., Lee, B. H., Choi, S. H., Jung, S. W., Kim, H. S., Lee, J. H., Hwang, S. H., Pyo, M. K., Kim, H. C. and Nah, S. Y. (2015) Differential effects of quercetin glycosides on GABAC receptor channel activity. Arch. Pharm. Res. 38, 108-114. https://doi.org/10.1007/s12272-014-0409-2
  23. Lee, B. H., Jeong, S. M., Lee, J. H., Kim, J. H., Yoon, I. S., Lee, J. H., Choi, S. H., Lee, S. M., Chang, C. G., Kim, H. C., Han, Y., Paik, H. D., Kim, Y. and Nah, S. Y. (2005) Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I. Mol. Cells 20, 69-73.
  24. Lee, B. H., Lee, J. H., Yoon, I. S., Lee, J. H., Choi, S. H., Pyo, M. K., Jeong, S. M., Choi, W. S., Shin, T. J., Lee, S. M., Rhim, H., Park, Y. S., Han, Y. S., Paik, H. D., Cho, S. G., Kim, C. H., Lim, Y. H. and Nah, S. Y. (2007) Human glycine alpha1 receptor inhibition by quercetin is abolished or inversed by alpha267 mutations in transmembrane domain 2. Brain Res. 1161, 1-10. https://doi.org/10.1016/j.brainres.2007.05.057
  25. Lee, B. H., Choi, S. H., Shin, T. J., Pyo, M. K., Hwang, S. H., Kim, B. R., Lee, S. M., Lee, J. H., Kim, H. C., Park, H. Y., Rhim, H. and Nah, S. Y. (2010) Quercetin enhances human ${\alpha}7$ nicotinic acetylcholine receptor-mediated ion current through interactions with $Ca^{2+}$ binding sites. Mol. Cells 30, 245-253.
  26. Lena, C. and Changeux, J. P. (1997) Pathological mutations of nicotinic receptors and nicotine-based therapies for brain disorders. Curr. Opin. Neurobiol. 7, 674-682. https://doi.org/10.1016/S0959-4388(97)80088-8
  27. Marder, M., Viola, H., Wasowski, C., Wolfman, C., Waterman, P. G., Cassels, B. K., Medina, J. G. and Paladini, A. C. (1996) 6-Bromoflavone, a high affinity ligand for the central benzodiazepine receptors is a member of a family of active flavonoids. Biochem. Biophys. Res. Commun. 223, 384-389. https://doi.org/10.1006/bbrc.1996.0903
  28. Medina, J. H., Viola, H., Wolfman, C,, Marder, M., Wasowski, C., Calvo, D. and Paladini, A. C. (1997) Overview--flavonoids: a new family of benzodiazepine receptor ligands. Neurochem. Res. 22, 419-425. https://doi.org/10.1023/A:1027303609517
  29. Murota, K. and Terao, J. (2003) Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism. Arch. Biochem. Biophys. 417, 12-17. https://doi.org/10.1016/S0003-9861(03)00284-4
  30. Nashmi, R. and Lester, H. A. (2006) CNS localization of neuronal nicotinic receptors. J. Mol. Neurosci. 30, 181-184. https://doi.org/10.1385/JMN:30:1:181
  31. Nemeth, K. and Piskula, M. K. (2007) Food content, processing, absorption and metabolism of onion flavonoids. Crit. Rev. Food Sci. Nutr. 47, 397-409. https://doi.org/10.1080/10408390600846291
  32. Oyama, Y., Fuchs, P. A., Katayama, N. and Noda, K. (1994) Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and $Ca^{2+}$-loaded brain neurons. Brain Res. 635, 125-129. https://doi.org/10.1016/0006-8993(94)91431-1
  33. Picq, M., Cheav, S. L. and Prigent, A. F. (1991) Effect of two flavonoid compounds on central nervous system. Analgesic activity. Life Sci. 49, 1979-1988. https://doi.org/10.1016/0024-3205(91)90640-W
  34. Revah, F., Bertrand, D., Galzi, J. L., Devillers-Thiery, A., Mulle, C., Hussy, N., Bertrand, S., Ballivet, M. and Changeux, J. P. (1991) Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor. Nature 353, 846-849. https://doi.org/10.1038/353846a0
  35. Seguela, P., Wadiche, J., Dineley-Miller, K., Dani, J. A. and Patrick, J. W. (1993) Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J. Neurosci. 13, 596-604. https://doi.org/10.1523/JNEUROSCI.13-02-00596.1993
  36. Speroni, E. and Minghetti, A. (1988) Neuropharmacological activity of extracts from Passiflora incarnata. Planta Med. 54, 488-491. https://doi.org/10.1055/s-2006-962525
  37. Weiland, S., Bertrand, D. and Leonard, S. (2000) Neuronal nicotinic acetylcholine receptors: from the gene to the disease. Behav. Brain Res. 113, 43-56. https://doi.org/10.1016/S0166-4328(00)00199-6
  38. Yao, Y., Han, D. D., Zhang, T. and Yang, Z. (2010) Quercetin improves cognitive deficits in rats with chronic cerebral ischemia and inhibits voltage-dependent sodium channels in hippocampal CA1 pyramidal neurons. Phytother. Res. 24, 136-140. https://doi.org/10.1002/ptr.2902

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