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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

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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.

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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.

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Authors and Affiliations

  1. Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Han Zhang & Xiumei Goa

  2. Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Nobuyuki Yanagihara, Yumiko Toyohira, Keita Takahashi, Hirohide Inagaki & Xiaoja Li

  3. Shared-Use Research Center, University of Occupational & Environmental Health, University of Occupational & Environmental Health, Japan

    Noriaki Satoh

  4. Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan

    Masato Tsutsui

  5. Department of Hospital Pharmacy, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Kojiro Takahaishi

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  1. Han Zhang
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  2. Nobuyuki Yanagihara
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Correspondence to Nobuyuki Yanagihara.

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Zhang, H., Yanagihara, N., Toyohira, Y. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 387, 15–22 (2014). https://doi.org/10.1007/s00210-013-0916-6

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  • DOI: https://doi.org/10.1007/s00210-013-0916-6

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