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


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.


Adrenal medulla Catecholamine synthesis Citrus flavonoid Nobiletin Phosphorylation Tyrosine hydroxylase 



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.


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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

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