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Upregulation of norepinephrine transporter function by prolonged exposure to nicotine in cultured bovine adrenal medullary cells

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Abstract

Nicotine acts on nicotinic acetylcholine receptors in the adrenal medulla and brain, thereby stimulating the release of monoamines such as norepinephrine (NE). In the present study, we examined the effects of prolonged exposure to nicotine on NE transporter (NET) activity in cultured bovine adrenal medullary cells. Treatment of adrenal medullary cells with nicotine increased [3H]NE uptake in both a time- (1–5 days) and concentration-dependent (0.1–10 μM) manner. Kinetic analysis showed that nicotine induced an increase in the V max of [3H]NE uptake with little change in K m. This increase in NET activity was blocked by cycloheximide, an inhibitor of ribosomal protein synthesis, but not by actinomycin D, a DNA-dependent RNA polymerase inhibitor. [3H]NE uptake induced by nicotine was strongly inhibited by hexamethonium and mecamylamine but not by α-bungarotoxin, and was abolished by elimination of Ca2+ from the culture medium. KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, attenuated not only nicotine-induced [3H]NE uptake but also 45Ca2+ influx in the cells. The present findings suggest that long-term exposure to nicotine increases NET activity through a Ca2+-dependent post-transcriptional process in the adrenal medulla.

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Abbreviations

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

DMSO:

Dimethyl sulfoxide

DMI:

Desipramine

Eagle’s MEM:

Eagle’s minimum essential medium

KRH:

Krebs–Ringer HEPES

KRP:

Krebs–Ringer phosphate

NE:

Norepinephrine

NET:

Norepinephrine transporter

nAChR:

Nicotinic acetylcholine receptor

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Acknowledgement

This research was supported, in part, by a grant from the Smoking Research Foundation, Grant-in-Aids (20611020 and 20590129) for Scientific Research (C) from the Japan Society for the Promotion of Science, and a grant from the University of Occupational and Environmental Health for Advanced Research. We are grateful to Ms. Satomi Sonoda and Ms. Mayumi Yamashita for her experimental assistance.

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Authors and Affiliations

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

    Hideaki Itoh, Satoru Saeki & Kenji Hachisuka

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

    Hideaki Itoh, Yumiko Toyohira, Susumu Ueno, Han Zhang, Yumi Furuno & Nobuyuki Yanagihara

  3. Department of Hospital Pharmacy, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8556, Japan

    Kojiro Takahashi

  4. Department of Pharmacology, Faculty of Medicine, University of the Ryukyus, 207, Uehara, Nishihara-Cho, Okinawa, 903-0215, Japan

    Masato Tsutsui

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  1. Hideaki Itoh
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  2. Yumiko Toyohira
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  10. Nobuyuki Yanagihara
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Correspondence to Nobuyuki Yanagihara.

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Itoh, H., Toyohira, Y., Ueno, S. et al. Upregulation of norepinephrine transporter function by prolonged exposure to nicotine in cultured bovine adrenal medullary cells. Naunyn-Schmied Arch Pharmacol 382, 235–243 (2010). https://doi.org/10.1007/s00210-010-0540-7

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  • DOI: https://doi.org/10.1007/s00210-010-0540-7

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