Authors
Yukihiro Tsuchiya, Takahisa Nakane, Shoma Araki, Tsuyoshi Takata, Hideshi Ihara, Yasuo Watanabe
Published in
Journal of pharmacological sciences. Volume 162. Issue 3. Pages 232-237. Epub Sep 10, 2026.
Abstract
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 Ca2+ level increase without affecting ATP-, KCl-, or Ca2+ ionophore-induced Ca2+ responses, suggesting selective inhibition of nicotinic receptor-mediated Ca2+ 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.
PMID:
42810780
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.
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