Dual effects of nobiletin, a citrus polymethoxy flavone, on catecholamine secretion in cultured bovine adrenal medullary cells

• Published in: Journal of neurochemistry 2010-08, Vol.114 (4), p.1030-1038
• Main Authors: Zhang, Han, Toyohira, Yumiko, Ueno, Susumu, Shinohara, Yuko, Itoh, Hideaki, Furuno, Yumi, Yamakuni, Tohru, Tsutsui, Masato, Takahashi, Kojiro, Yanagihara, Nobuyuki
• Format: Article
• Language: English
• Subjects: adrenal medulla; Adrenal Medulla - drug effects; Adrenal Medulla - innervation; Adrenal Medulla - secretion; Adrenals. Interrenals; Adrenomedullary hormones. Regulation; Animals; Antioxidants - pharmacology; Biochemistry; Biological and medical sciences; Calcium; Calcium - antagonists & inhibitors; Calcium - metabolism; Calcium Channels - metabolism; Calcium Signaling - drug effects; Calcium Signaling - physiology; catecholamine secretion; Catecholamines - antagonists & inhibitors; Catecholamines - metabolism; Catecholamines - secretion; Cattle; Cell culture; Cells, Cultured; Chemical compounds; Chromaffin Cells - drug effects; Chromaffin Cells - metabolism; Chromaffin Cells - secretion; Citrus; Citrus - chemistry; Dose-Response Relationship, Drug; dual effects; Flavones - pharmacology; Fundamental and applied biological sciences. Psychology; ion influx; Isolated neuron and nerve. Neuroglia; Neurology; nobiletin; Oocytes; Plant Extracts - pharmacology; Sodium Channels - metabolism; Sodium-Calcium Exchanger - antagonists & inhibitors; Sodium-Calcium Exchanger - metabolism; Vertebrates: endocrinology; Vertebrates: nervous system and sense organs; voltage-dependent Ca²⁺ channels; voltage‐dependent Ca2+ channels; Xenopus
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06840.x

J. Neurochem. (2010) 114, 1030-1038. Nobiletin, a compound of polymethoxy flavones found in citrus fruits, possesses a wide range of pharmacological activities. Here we report the effects of nobiletin on catecholamine secretion in cultured bovine adrenal medullary cells. Nobiletin (1.0-100 μM) concentration-dependently stimulated catecholamine secretion and ⁴⁵Ca²⁺ influx. Its stimulatory effect of nobiletin on catecholamine secretion was abolished by deprivation of extracellular Ca²⁺ and partially inhibited by specific inhibitors of voltage-dependent Ca²⁺ channels and Na⁺/Ca²⁺ exchangers. On the other hand, nobiletin suppressed catecholamine secretion and ²²Na⁺ and ⁴⁵Ca²⁺ influx induced by acetylcholine, an agonist of nicotinic acetylcholine receptors, in a concentration-dependent manner. It also inhibited catecholamine secretion, ²²Na⁺ influx and/or ⁴⁵Ca²⁺ influx induced by veratridine, an activator of voltage-dependent Na⁺ channels, and 56 mM K⁺, an activator of voltage-dependent Ca²⁺ channels. In Xenopus oocytes expressing α3β4 neuronal acetylcholine receptors, nobiletin directly inhibited the current evoked by acetylcholine in a concentration-dependent manner similar to that observed in catecholamine secretion. The present findings suggest that nobiletin, by itself, stimulates catecholamine secretion via activation of voltage-dependent Ca²⁺ channels or Na⁺/Ca²⁺ exchangers, whereas it inhibits catecholamine secretion induced by acetylcholine through the suppression of Na⁺ influx and Ca²⁺ influx in cultured bovine adrenal medullary cells.