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Natural and synthetic flavonoid modulation of TRPC5 channels
Author(s) -
Naylor Jacqueline,
Minard Aisling,
Gaunt Hannah J,
Amer Mohamed S,
Wilson Lesley A,
Migliore Marco,
Cheung Sin Y,
Rubaiy Hussein N,
Blythe Nicola M,
Musialowski Katie E,
Ludlow Melanie J,
Evans William D,
Green Ben L,
Yang Hongjun,
You Yun,
Li Jing,
Fishwick Colin W G,
Muraki Katsuhiko,
Beech David J,
Bon Robin S
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13387
Subject(s) - trpc5 , chemistry , galangin , agonist , kaempferol , biochemistry , quercetin , ion channel , biophysics , receptor , trpc1 , biology , antioxidant
Background and Purpose The TRPC5 proteins assemble to create calcium‐permeable, non‐selective, cationic channels. We sought novel modulators of these channels through studies of natural products. Experimental Approach Intracellular calcium measurements and patch clamp recordings were made from cell lines. Compounds were generated by synthetic chemistry. Key Results Through a screen of natural products used in traditional Chinese medicines, the flavonol galangin was identified as an inhibitor of lanthanide‐evoked calcium entry in TRPC5 overexpressing HEK 293 cells (IC 50 0.45 μM). Galangin also inhibited lanthanide‐evoked TRPC5‐mediated current in whole‐cell and outside‐out patch recordings. In differentiated 3T3‐L1 cells, it inhibited constitutive and lanthanide‐evoked calcium entry through endogenous TRPC5‐containing channels. The related natural flavonols, kaempferol and quercetin were less potent inhibitors of TRPC5. Myricetin and luteolin lacked effect, and apigenin was a stimulator. Based on structure–activity relationship studies with natural and synthetic flavonols, we designed 3,5,7‐trihydroxy‐2‐(2‐bromophenyl)‐4 H ‐chromen‐4‐one (AM12), which inhibited lanthanide‐evoked TRPC5 activity with an IC 50 of 0.28 μM. AM12 also inhibited TRPC5 activity evoked by the agonist (−)‐Englerin A and was effective in excised outside‐out membrane patches, suggesting a relatively direct effect. It inhibited TRPC4 channels similarly, but its inhibitory effect on TRPC1–TRPC5 heteromeric channels was weaker. Conclusions and Implications The data suggest that galangin (a natural product from the ginger family) is a TRPC5 inhibitor and that other natural and synthetic flavonoids contain antagonist or agonist capabilities at TRPC5 and closely related channels depending on the substitution patterns of both the chromone core and the phenyl ring.