Nobiletin differentially regulates muscarinic and nicotinic receptor–mediated ERK signaling

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Nobiletin, a citrus polymethoxyflavone with neuroprotective properties, activates extracellular signal–regulated kinase 1/2 (ERK1/2); however, its effects on cholinergic receptor–mediated ERK signaling remain unclear. This study aimed to investigate the effects of nobiletin on the muscarinic and nicotinic receptor–dependent ERK signaling in neuronal nitric oxide synthase–expressing PC12 cells. The results showed that nobiletin inhibited acetylcholine- and bethanechol-induced ERK1/2 phosphorylation, an effect attenuated by increasing agonist concentrations, consistent with a competitive-like pattern. In contrast, nobiletin inhibited nicotine-induced ERK1/2 phosphorylation, which was not overcome by increasing nicotine concentrations, consistent with a noncompetitive-like pattern. Nobiletin also selectively suppressed nicotine-induced intracellular Ca 2+ level increase without affecting ATP-, KCl-, or Ca 2+ ionophore–induced Ca 2+ responses, suggesting selective inhibition of nicotinic receptor–mediated Ca 2+ entry. Although it modestly increased basal ERK1/2 phosphorylation, nobiletin suppressed both muscarinic and nicotinic receptor–mediated ERK1/2 activation. These findings suggest that nobiletin differentially regulates muscarinic and nicotinic receptor–mediated ERK signaling, reveal novel pharmacological actions of nobiletin, and provide insight into the regulation of neuronal cholinergic signaling by citrus polymethoxyflavones.