Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Mar;82(3):1266–1277. doi: 10.1016/S0006-3495(02)75483-0

Effects of quercetin on single Ca(2+) release channel behavior of skeletal muscle.

Eun Hui Lee 1, Gerhard Meissner 1, Do Han Kim 1
PMCID: PMC1301930  PMID: 11867444

Abstract

Quercetin, a bioflavonoid, is known to affect Ca(2+) fluxes in sarcoplasmic reticulum, although its direct effect on Ca(2+) release channel (CRC) in sarcoplasmic reticulum has remained to be elucidated. The present study examined the effect of quercetin on the behavior of single skeletal CRC in planar lipid bilayer. The effect of caffeine was also studied for comparison. At very low [Ca(2+)](cis) (80 pM), quercetin activated CRC marginally, whereas at elevated [Ca(2+)](cis) (10 microM), both open probability (P(o)) and sensitivity to the drug increased markedly. Caffeine showed a similar tendency. Analysis of lifetimes for single CRC showed that quercetin and caffeine led to different mean open-time and closed-time constants and their proportions. Addition of 10 microM ryanodine to CRC activated by quercetin or caffeine led to the typical subconductance state (approximately 54%) and a subsequent addition of 5 microM ruthenium red completely blocked CRC activity. When 6 microM quercetin and 3 mM caffeine were added together to the cis side of CRC, a time-dependent increase of P(o) was observed (from mode 1 (0.376 +/- 0.043, n = 5) to mode 2 (0.854 +/- 0.062, n = 5)). On the other hand, no further activation was observed when quercetin was added after caffeine. Quercetin affected only the ascending phase of the bell-shaped Ca(2+) activation/inactivation curve, whereas caffeine affected both ascending and descending phases. [(3)H]ryanodine binding to sarcoplasmic reticulum showed that channel activity increased more by both quercetin and caffeine than by caffeine alone. These characteristic differences in the modes of activation of CRC by quercetin and caffeine suggest that the channel activation mechanisms and presumably the binding sites on CRC are different for the two drugs.

Full Text

The Full Text of this article is available as a PDF (403.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Armisén R., Sierralta J., Vélez P., Naranjo D., Suárez-Isla B. A. Modal gating in neuronal and skeletal muscle ryanodine-sensitive Ca2+ release channels. Am J Physiol. 1996 Jul;271(1 Pt 1):C144–C153. doi: 10.1152/ajpcell.1996.271.1.C144. [DOI] [PubMed] [Google Scholar]
  2. Beretz A., Cazenave J. P., Anton R. Inhibition of aggregation and secretion of human platelets by quercetin and other flavonoids: structure-activity relationships. Agents Actions. 1982 Jul;12(3):382–387. doi: 10.1007/BF01965408. [DOI] [PubMed] [Google Scholar]
  3. Berton G., Schneider C., Romeo D. Inhibition by quercetin of activation of polymorphonuclear leucocyte functions. Stimulus-specific effects. Biochim Biophys Acta. 1980;595(1):47–55. doi: 10.1016/0005-2736(80)90246-1. [DOI] [PubMed] [Google Scholar]
  4. Bindoli A., Valente M., Cavallini L. Inhibitory action of quercetin on xanthine oxidase and xanthine dehydrogenase activity. Pharmacol Res Commun. 1985 Sep;17(9):831–839. doi: 10.1016/0031-6989(85)90041-4. [DOI] [PubMed] [Google Scholar]
  5. Buck E., Zimanyi I., Abramson J. J., Pessah I. N. Ryanodine stabilizes multiple conformational states of the skeletal muscle calcium release channel. J Biol Chem. 1992 Nov 25;267(33):23560–23567. [PubMed] [Google Scholar]
  6. Bull R., Marengo J. J., Suárez-Isla B. A., Donoso P., Sutko J. L., Hidalgo C. Activation of calcium channels in sarcoplasmic reticulum from frog muscle by nanomolar concentrations of ryanodine. Biophys J. 1989 Oct;56(4):749–756. doi: 10.1016/S0006-3495(89)82722-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carroll S., Skarmeta J. G., Yu X., Collins K. D., Inesi G. Interdependence of ryanodine binding, oligomeric receptor interactions, and Ca2+ release regulation in junctional sarcoplasmic reticulum. Arch Biochem Biophys. 1991 Oct;290(1):239–247. doi: 10.1016/0003-9861(91)90615-p. [DOI] [PubMed] [Google Scholar]
  8. Deneke S. M., Fanburg B. L. Regulation of cellular glutathione. Am J Physiol. 1989 Oct;257(4 Pt 1):L163–L173. doi: 10.1152/ajplung.1989.257.4.L163. [DOI] [PubMed] [Google Scholar]
  9. Deters D. W., Racker E., Nelson N., Nelson H. Partial resolution of the enzymes catalyzing photophosphorylation. XV. Approaches to the active site of coupling factor I. J Biol Chem. 1975 Feb 10;250(3):1041–1047. [PubMed] [Google Scholar]
  10. Ebashi S., Endo M. Calcium ion and muscle contraction. Prog Biophys Mol Biol. 1968;18:123–183. doi: 10.1016/0079-6107(68)90023-0. [DOI] [PubMed] [Google Scholar]
  11. Endo M. Calcium release from the sarcoplasmic reticulum. Physiol Rev. 1977 Jan;57(1):71–108. doi: 10.1152/physrev.1977.57.1.71. [DOI] [PubMed] [Google Scholar]
  12. Fewtrell C. M., Gomperts B. D. Effect of flavone inhibitors of transport ATPases on histamine secretion from rat mast cells. Nature. 1977 Feb 17;265(5595):635–636. doi: 10.1038/265635a0. [DOI] [PubMed] [Google Scholar]
  13. Formica J. V., Regelson W. Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol. 1995 Dec;33(12):1061–1080. doi: 10.1016/0278-6915(95)00077-1. [DOI] [PubMed] [Google Scholar]
  14. Gschwendt M., Horn F., Kittstein W., Marks F. Inhibition of the calcium- and phospholipid-dependent protein kinase activity from mouse brain cytosol by quercetin. Biochem Biophys Res Commun. 1983 Dec 16;117(2):444–447. doi: 10.1016/0006-291x(83)91220-2. [DOI] [PubMed] [Google Scholar]
  15. Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol. 1983 Apr 1;32(7):1141–1148. doi: 10.1016/0006-2952(83)90262-9. [DOI] [PubMed] [Google Scholar]
  16. Hernández-Cruz A., Díaz-Muñoz M., Gómez-Chavarín M., Cañedo-Merino R., Protti D. A., Escobar A. L., Sierralta J., Suárez-Isla B. A. Properties of the ryanodine-sensitive release channels that underlie caffeine-induced Ca2+ mobilization from intracellular stores in mammalian sympathetic neurons. Eur J Neurosci. 1995 Aug 1;7(8):1684–1699. doi: 10.1111/j.1460-9568.1995.tb00690.x. [DOI] [PubMed] [Google Scholar]
  17. Kim D. H., Mkparu F., Kim C. R., Caroll R. F. Alteration of Ca2+ release channel function in sarcoplasmic reticulum of pressure-overload-induced hypertrophic rat heart. J Mol Cell Cardiol. 1994 Nov;26(11):1505–1512. doi: 10.1006/jmcc.1994.1169. [DOI] [PubMed] [Google Scholar]
  18. Kim D. H., Ohnishi S. T., Ikemoto N. Kinetic studies of calcium release from sarcoplasmic reticulum in vitro. J Biol Chem. 1983 Aug 25;258(16):9662–9668. [PubMed] [Google Scholar]
  19. Kirino Y., Shimizu H. Ca2+-induced Ca2+ release from fragmented sarcoplasmic reticulum: a comparison with skinned muscle fiber studies. J Biochem. 1982 Oct;92(4):1287–1296. doi: 10.1093/oxfordjournals.jbchem.a134047. [DOI] [PubMed] [Google Scholar]
  20. Kuriki Y., Racker E. Inhibition of (Na+, K+)adenosine triphosphatase and its partial reactions by quercetin. Biochemistry. 1976 Nov 16;15(23):4951–4956. doi: 10.1021/bi00668a001. [DOI] [PubMed] [Google Scholar]
  21. Meissner G., Darling E., Eveleth J. Kinetics of rapid Ca2+ release by sarcoplasmic reticulum. Effects of Ca2+, Mg2+, and adenine nucleotides. Biochemistry. 1986 Jan 14;25(1):236–244. doi: 10.1021/bi00349a033. [DOI] [PubMed] [Google Scholar]
  22. Meissner G., Rios E., Tripathy A., Pasek D. A. Regulation of skeletal muscle Ca2+ release channel (ryanodine receptor) by Ca2+ and monovalent cations and anions. J Biol Chem. 1997 Jan 17;272(3):1628–1638. doi: 10.1074/jbc.272.3.1628. [DOI] [PubMed] [Google Scholar]
  23. Meissner G. Ryanodine receptor/Ca2+ release channels and their regulation by endogenous effectors. Annu Rev Physiol. 1994;56:485–508. doi: 10.1146/annurev.ph.56.030194.002413. [DOI] [PubMed] [Google Scholar]
  24. Miller C., Racker E. Ca++-induced fusion of fragmented sarcoplasmic reticulum with artificial planar bilayers. J Membr Biol. 1976;30(3):283–300. doi: 10.1007/BF01869673. [DOI] [PubMed] [Google Scholar]
  25. Nishino H., Naito E., Iwashima A., Tanaka K., Matsuura T., Fujiki H., Sugimura T. Interaction between quercetin and Ca2+-calmodulin complex: possible mechanism for anti-tumor-promoting action of the flavonoid. Gan. 1984 Apr;75(4):311–316. [PubMed] [Google Scholar]
  26. Oba T., Koshita M., Van Helden D. F. Modulation of frog skeletal muscle Ca2+ release channel gating by anion channel blockers. Am J Physiol. 1996 Sep;271(3 Pt 1):C819–C824. doi: 10.1152/ajpcell.1996.271.3.C819. [DOI] [PubMed] [Google Scholar]
  27. Palade P., Mitchell R. D., Fleischer S. Spontaneous calcium release from sarcoplasmic reticulum. General description and effects of calcium. J Biol Chem. 1983 Jul 10;258(13):8098–8107. [PubMed] [Google Scholar]
  28. Pessah I. N., Zimanyi I. Characterization of multiple [3H]ryanodine binding sites on the Ca2+ release channel of sarcoplasmic reticulum from skeletal and cardiac muscle: evidence for a sequential mechanism in ryanodine action. Mol Pharmacol. 1991 May;39(5):679–689. [PubMed] [Google Scholar]
  29. Robak J., Gryglewski R. J. Flavonoids are scavengers of superoxide anions. Biochem Pharmacol. 1988 Mar 1;37(5):837–841. doi: 10.1016/0006-2952(88)90169-4. [DOI] [PubMed] [Google Scholar]
  30. Rousseau E., Ladine J., Liu Q. Y., Meissner G. Activation of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds. Arch Biochem Biophys. 1988 Nov 15;267(1):75–86. doi: 10.1016/0003-9861(88)90010-0. [DOI] [PubMed] [Google Scholar]
  31. Rousseau E., Meissner G. Single cardiac sarcoplasmic reticulum Ca2+-release channel: activation by caffeine. Am J Physiol. 1989 Feb;256(2 Pt 2):H328–H333. doi: 10.1152/ajpheart.1989.256.2.H328. [DOI] [PubMed] [Google Scholar]
  32. Rousseau E., Smith J. S., Meissner G. Ryanodine modifies conductance and gating behavior of single Ca2+ release channel. Am J Physiol. 1987 Sep;253(3 Pt 1):C364–C368. doi: 10.1152/ajpcell.1987.253.3.C364. [DOI] [PubMed] [Google Scholar]
  33. Ríos E., Pizarro G. Voltage sensor of excitation-contraction coupling in skeletal muscle. Physiol Rev. 1991 Jul;71(3):849–908. doi: 10.1152/physrev.1991.71.3.849. [DOI] [PubMed] [Google Scholar]
  34. Shoshan V., Campbell K. P., MacLennan D. H., Frodis W., Britt B. A. Quercetin inhibits Ca2+ uptake but not Ca2+ release by sarcoplasmic reticulum in skinned muscle fibers. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4435–4438. doi: 10.1073/pnas.77.8.4435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shoshan V., MacLennan D. H. Quercetin interaction with the (Ca2+ + Mg2+)-ATPase of sarcoplasmic reticulum. J Biol Chem. 1981 Jan 25;256(2):887–892. [PubMed] [Google Scholar]
  36. Shoshan V., Shahak Y., Shavit N. Quercetin interaction with the chloroplast ATPase complex. Biochim Biophys Acta. 1980 Jul 8;591(2):421–433. doi: 10.1016/0005-2728(80)90173-5. [DOI] [PubMed] [Google Scholar]
  37. Sitsapesan R., Williams A. J. Mechanisms of caffeine activation of single calcium-release channels of sheep cardiac sarcoplasmic reticulum. J Physiol. 1990 Apr;423:425–439. doi: 10.1113/jphysiol.1990.sp018031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Smith J. S., Coronado R., Meissner G. Single channel measurements of the calcium release channel from skeletal muscle sarcoplasmic reticulum. Activation by Ca2+ and ATP and modulation by Mg2+. J Gen Physiol. 1986 Nov;88(5):573–588. doi: 10.1085/jgp.88.5.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Watras J., Glezen S., Seifert C., Katz A. M. Quercetin stimulation of calcium release from rabbit skeletal muscle sarcoplasmic reticulum. Life Sci. 1983 Jan 17;32(3):213–219. doi: 10.1016/0024-3205(83)90033-4. [DOI] [PubMed] [Google Scholar]
  40. Zable A. C., Favero T. G., Abramson J. J. Glutathione modulates ryanodine receptor from skeletal muscle sarcoplasmic reticulum. Evidence for redox regulation of the Ca2+ release mechanism. J Biol Chem. 1997 Mar 14;272(11):7069–7077. doi: 10.1074/jbc.272.11.7069. [DOI] [PubMed] [Google Scholar]
  41. Zahradníková A., Zahradník I. Description of modal gating of the cardiac calcium release channel in planar lipid membranes. Biophys J. 1995 Nov;69(5):1780–1788. doi: 10.1016/S0006-3495(95)80048-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES