Open AccessSubtype‐selective inhibition of acid‐sensing ion channel 3 by a natural flavonoid
Author(s) -
Yan XiaoGang,
Li WeiGuang,
Qi Xin,
Zhu JiaJie,
Huang Chen,
Han ShaoLing,
Jiang Qin,
Xu TianLe,
Liu JianHua
Publication year - 2019
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12979
Subject(s) - acid sensing ion channel , homomeric , ion channel , chemistry , flavonoid , pharmacology , biochemistry , biophysics , medicine , biology , receptor , protein subunit , gene , antioxidant
Summary Aims Acid‐sensing ion channels ( ASIC s) are extracellular proton‐gated cation channels that have been implicated in multiple physiological and pathological processes, and peripheral ASIC 3 prominently participate into the pathogenesis of chronic pain, itch, and neuroinflammation, which necessitates the need for discovery and development of novel modulators in a subtype‐specific manner. Methods Whole‐cell patch clamp recordings and behavioral assays were used to examine the effect of several natural compounds on the ASIC ‐mediated currents and acid‐induced nocifensive behavior, respectively. Results We identified a natural flavonoid compound, (‐)‐epigallocatechin gallate ( EGCG , compound 11 ), that acts as a potent inhibitor for the ASIC 3 channel in an isoform‐specific way. The compound 11 inhibited ASIC 3 currents with an apparent half maximal inhibitory concentration of 13.2 μmol/L when measured at pH 5.0. However, at the concentration up to 100 μmol/L, the compound 11 had no significant impacts on the homomeric ASIC 1a, 1b, and 2a channels. In contrast to most of the known ASIC inhibitors that usually bear either basic or carboxylic groups, the compound 11 belongs to the polyphenolic family. In compound 11 , both the chirality and the 3‐hydroxyl group of its pyrogallol part, in addition to the integrity of the gallate part, are crucial for the inhibitory efficacy. Finally, EGCG was found significantly to decrease the acid‐induced nocifensive behavior in mice. Conclusion Taken together, these results thus defined a novel backbone structure for small molecule drug design targeting ASIC 3 channels to treat pain‐related diseases.