Advertisement

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 387, Issue 1, pp 15–22 | Cite as

Stimulatory effect of nobiletin, a citrus polymethoxy flavone, on catecholamine synthesis through Ser19 and Ser40 phosphorylation of tyrosine hydroxylase in cultured bovine adrenal medullary cells

  • Han Zhang
  • Nobuyuki YanagiharaEmail author
  • Yumiko Toyohira
  • Keita Takahashi
  • Hirohide Inagaki
  • Noriaki Satoh
  • Xiaoja Li
  • Xiumei Goa
  • Masato Tsutsui
  • Kojiro Takahaishi
Original Article

Abstract

We previously reported the dual effects of nobiletin, a compound of polymethoxy flavones found in citrus fruits, on catecholamine secretion in cultured bovine adrenal medullary cells. Here, we report the effects of nobiletin on catecholamine synthesis in the cells. Nobiletin increased the synthesis of 14C-catecholamines from [14C]tyrosine in a time (20–30 min)- and concentration (1.0–100 μM)-dependent manner. Nobiletin (10–100 μM) also activated tyrosine hydroxylase activity. The stimulatory effect of nobiletin on 14C-catecholamine synthesis was not observed when extracellular Ca2+ was not present in the incubation medium. Protein kinase inhibitors including H-89, an inhibitor of cyclic AMP-dependent protein kinase, and KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, suppressed the stimulatory effects of nobiletin on catecholamine synthesis as well as tyrosine hydroxylase activity. Nobiletin also induced the phosphorylation of tyrosine hydroxylase at Ser19 and Ser40. Nobiletin (1.0–100 μM) inhibited 14C-catecholamine synthesis induced by acetylcholine. The present findings suggest that nobiletin, by itself, stimulates catecholamine synthesis through tyrosine hydroxylase phosphorylation at Ser19 and Ser40, whereas it inhibits catecholamine synthesis induced by acetylcholine in bovine adrenal medulla.

Keywords

Adrenal medulla Catecholamine synthesis Citrus flavonoid Nobiletin Phosphorylation Tyrosine hydroxylase 

Notes

Acknowledgments

This research was supported, in part, by Grant-in-Aids (23617035, 23590159, 23617036, and 24890286) for Scientific Research (C) from the Japan Society for the Promotion of Science.

Conflict of interest

The authors have no conflict of interest to report.

References

  1. Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, Stefanek M, Sood AK (2006) The influence of bio-behavioral factors on tumor biology: pathways and mechanisms. Nat Rev Cancer 6:240–248PubMedCentralPubMedCrossRefGoogle Scholar
  2. Bocco A, Cuvelier ME, Richard H, Berset C (1998) Antioxidant activity and phenolic composition of citrus peel and seed extracts. J Agric Food Chem 46:2123–2129CrossRefGoogle Scholar
  3. Bobrovskaya L, Cheah TB, Bunn SJ, Dunkley PR (1998) Tyrosine hydroxylase in bovine adrenal chromaffin cells: angiotensin II-stimulated activity and phosphorylation of Ser19, Ser31 and Ser40. J Neurochem 70:2565–2573PubMedCrossRefGoogle Scholar
  4. Cox ME, Parsons S (1997) Roles for protein kinase C and mitogen-activated protein kinase in nicotine-induced secretion from bovine adrenal chromaffin cells. J Neurochem 69:1119–1130PubMedCrossRefGoogle Scholar
  5. Douglas WW, Rubin RP (1961) Mechanism of nicotinic action at the adrenal medulla: calcium as a link in stimulus-secretion coupling. Nature 192:1087–1089PubMedCrossRefGoogle Scholar
  6. Douglas WW, Rubin RP (1963) The mechanism of catecholamine release from the adrenal medulla and the role of calcium in stimulus-secretion coupling. J Physiol 167:288–310PubMedGoogle Scholar
  7. Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki E, Dickson PW (2004) Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 91:1025–1043PubMedCrossRefGoogle Scholar
  8. Freedman NJ, Lefkowitz RJ (2004) Anti-β1-adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Invest 113:1379–1382PubMedCentralPubMedGoogle Scholar
  9. Goldstein DS (2003) Catecholamines and stress. Endocr Regul 37:69–80PubMedGoogle Scholar
  10. Hara MR, Kovacs JJ, Whalen EJ, Rajagopal S, Strachan RT, Grant W, Towers AJ, Williams B, Lam CM, Xiao K, Shenoy SK, Gregory SG, Ahn S, Duckett DR, Lefkowitz RJ (2011) A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature 477:349–353PubMedCentralPubMedCrossRefGoogle Scholar
  11. Keogh R, Marley PD (1991) Regulation of cyclic AMP levels by calcium in bovine adrenal medullary cells. J Neurochem 57:1721–1728PubMedCrossRefGoogle Scholar
  12. Matsuzaki K, Yamakuni T, Hashimoto M, Haque AB, Shido O, Mimaki Y, Sashida Y, Ohizumi Y (2006) Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer’s disease model rats. Neurosci Lett 400:230–234PubMedCrossRefGoogle Scholar
  13. Mendoza IE, Schmachtenberg OS, Tonk E, Fuentealba J, Diaz-Raya P, Lagos VL, Garcia AG, Gardenas AM (2003) Depolarization-induced ERK phosphorylation depends on the cytosolic Ca2+ level rather than on the Ca2+ channels subtypes of chromaffin cells. J Neurochem 86:1477–1486PubMedCrossRefGoogle Scholar
  14. Middleton E Jr, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52:673–751PubMedGoogle Scholar
  15. Nagase H, Omae N, Omori A, Nakagawasai O, Tadano T, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y (2005a) Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities. Biochem Biophys Res Commun 337:1330–1336PubMedCrossRefGoogle Scholar
  16. Nagase H, Yamakuni T, Matsuzaki K (2005b) Mechanism of neurotrophic action of nobiletin in PC12D cells. Biochemistry 44:13683–13691PubMedCrossRefGoogle Scholar
  17. Nagatsu T, Levitt M, Udenfriend S (1964) Tyrosine hydroxylase: the initial step in norepinehrine biosynthesis. J Biol Chem 239:2910–2917PubMedGoogle Scholar
  18. Nakajima A, Yamakuni T, Haraguchi M, Omae N, Song SY, Kato C, Nakagawasai O, Tadano T, Yokosuka A, Mimaki Y, Sashida Y, Ohizumi Y (2007) Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. J Pharmacol Sci 105:122–126PubMedCrossRefGoogle Scholar
  19. Nogata Y, Sakamoto K, Shiratsuchi H, Ishii T, Yano M, Ohta H (2006) Flavonoid composition of fruit tissues of citrus species. Biosci Biotechnol Biochem 70:178–192PubMedCrossRefGoogle Scholar
  20. Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y (2008) Nobiletin, a citrus flavonoid, improves memory impairment and Aβ pathology in a transgenic mouse model of Alzheimer′s disease. J Pharmacol Exp Ther 326:739–744PubMedCrossRefGoogle Scholar
  21. Tsutsui M, Yanagihara N, Miyamaoto E, Kuroiwa A, Izumi F (1994) Correlation of activation of Ca2+ /calmodulin-dependent protein kinase II with catecholamine secretion and tyrosine hydroxylase activation in cultured bovine adrenal medullary cells. Mol Pharmacol 46:1041–1047PubMedGoogle Scholar
  22. Whitman SC, Kurowska EM, Manthey JA, Daugherty A (2005) Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis 178:25–32PubMedCrossRefGoogle Scholar
  23. Yamauchi T, Fujisawa H (1981) Tyrosine 3-monooxygenase is phosphorylated by Ca++-calmodulin-dependent protein kinase, followed by activation by activator protein. FEBS Lett 100:807–813Google Scholar
  24. Yanagihara N, Isosaki M, Ohuchi T, Oka M (1979) Muscarinic receptor-mediated increase in cyclic GMP level in isolated bovine adrenal medullary cells. FEBS Lett 105:296–298PubMedCrossRefGoogle Scholar
  25. Yanagihara N, Wada A, Izumi F (1987) Effects of α2-adrenergic agonists on carbachol-stimulated catecholamine synthesis in cultured bovine adrenal medullary cells. Biochem Pharmacol 36:3823–3828PubMedCrossRefGoogle Scholar
  26. Yanagihara N, Toyohira Y, Yamamoto H, Ohta Y, Tsutsui M, Miyamoto E, Izumi I (1994) Occurrence and activation of Ca2+/calmodulin-dependent protein kinase II and its endogenous substrates in bovine adrenal medullary cells. Mol Pharmacol 46:423–430PubMedGoogle Scholar
  27. Yanagihara N, Oishi Y, Yamamoto H, Tsutsui M, Kondoh J, Sugiura T, Miyamoto E, Izumi F (1996) Phosphorylation of chromogranin A and catecholamine secretion stimulated by elevation of intracellular Ca2+ in cultured bovine adrenal medullary cells. J Biol Chem 271:17463–17468PubMedCrossRefGoogle Scholar
  28. Zhang H, Toyohira Y, Ueno S, Shinohara Y, Itoh H, Furuno Y, Yamakuni T, Tsutsui M, Takahashi K, Yanagihara N (2010) Dual effects of nobiletin, a citrus polymethoxy flavones, on catecholamine secretion in cultured bovine adrenal medullary cells. J Neurochem 114:1030–1038PubMedGoogle Scholar
  29. Zigmond RE, Schwarzschild MA, Rittenhouse AR (1989) Acute regulation of tyrosine hydroxylase by nerve activity and by neurotransmitters via phosphorylation. Annu Rev Neurosci 12:415–461PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Han Zhang
    • 1
  • Nobuyuki Yanagihara
    • 2
    Email author
  • Yumiko Toyohira
    • 2
  • Keita Takahashi
    • 2
  • Hirohide Inagaki
    • 2
  • Noriaki Satoh
    • 3
  • Xiaoja Li
    • 2
  • Xiumei Goa
    • 1
  • Masato Tsutsui
    • 4
  • Kojiro Takahaishi
    • 5
  1. 1.Research Center of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
  2. 2.Department of Pharmacology, School of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
  3. 3.Shared-Use Research CenterUniversity of Occupational & Environmental HealthUniversity of Occupational & Environmental HealthJapan
  4. 4.Department of Pharmacology, Graduate School of MedicineUniversity of the RyukyusOkinawaJapan
  5. 5.Department of Hospital PharmacyUniversity of Occupational and Environmental HealthKitakyushuJapan

Personalised recommendations