Magnolol and honokiol target TRPC4 to regulate extracellular calcium influx and relax intestinal smooth muscle

• Published in: Journal of ethnopharmacology 2022-05, Vol.290, p.115105-115105, Article 115105
• Main Authors: Niu, Lin, Wang, Jie, Shen, Fukui, Gao, Jie, Jiang, Min, Bai, Gang
• Format: Article
• Language: English
• Subjects: Animals; Biphenyl Compounds - pharmacology; Calcium regulating; Calcium Signaling - drug effects; HEK293 Cells; Honokiol; Humans; Intestines - drug effects; Lignans - pharmacology; Magnolol; Male; Medicine, Chinese Traditional; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Myocytes, Smooth Muscle - drug effects; Rats; Rats, Sprague-Dawley; Smooth muscle relaxation; Transient receptor potential; TRPC Cation Channels - drug effects; TRPV Cation Channels - drug effects
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2022.115105

Magnolia officinalis Cortex (M. officinalis) is a classical traditional Chinese medicine (TCM) widely used to treat digestive system diseases. It effectively regulates gastrointestinal motility to improve abdominal pain, abdominal distension and other symptoms. Magnolol (MAG) and honokiol (HON) are the main pharmacodynamic components responsible for the gastrointestinal activity of M. officinalis. The transient receptor potential (TRP) family is highly expressed in the gastrointestinal tract and participates in the regulation of gastrointestinal motility, visceral hypersensitivity, visceral secretion and other physiological activities. In this study, the calcium-lowering mechanisms of MAG and HON contributing to the smooth muscle relaxation associated with TRP are discussed. The relaxation smooth muscle effects of MAG and HON were tested by the isolated intestine tone tests. A synthetic MAG probe (MAG-P) was used to target fishing for their possible target. The distribution of MAG on the smooth muscle was identified by a molecular tracer based on chemical biology. Ca2+ imaging and dual-luciferase reporter assays were used to determine the effects on the target proteins. Finally, the calcium-mediating effects of MAG and HON on smooth muscle cells and TRPC4-knockdown cells were compared to verify the potential mechanism. After confirming the smooth muscle relaxation in the small intestine induced by MAG and HON, the relaxation effect was identified mainly due to the downregulation of intracellular calcium by controlling external calcium influx. Although MAG and HON inhibited both TRPV4 and TRPC4 channels to reduce calcium levels, the inhibitory effect on TRPC4 channels is an important mechanism of their smooth muscle relaxation effect, since TRPC4 is widely expressed in the small intestinal smooth muscle cells. The inhibition of MAG and HON on TRPC4 channels contributes to the relaxation of intestinal smooth muscle. Magnolol (MAG) and honokiol (HON) induced small intestine smooth muscle relaxation to regulate gastrointestinal tract movement by inhibiting TRPC4 in smooth muscle cells. The graph created with BioRender (https://biorender.com). [Display omitted] •Magnolol and honokiol target TRPV4 and TRPC4 in small intestine.•TRPC4 is located in smooth muscle cell in both muscular layer and mucous layer different from TRPV4.•Magnolol, honokiol as TRPC4 inhibitors contribute to the intestinal relaxing effects.