title: Ginsenoside Rb1, a novel activator of the TMEM16A chloride channel, augments the contraction of guinea pig ileum.
abstract: Calcium-activated chloride channels (CaCCs) play important roles in many physiological processes, and the molecular basis of CaCCs has been identified as TMEM16A in many cell types. It is well established that TMEM16A is a drug target in many diseases, including cystic fibrosis, hypertension, asthma, and various tumors. Therefore, identifying potent and specific modulators of the TMEM16A channel is crucial. In this study, we identified the first natural activator of TMEM16A from traditional Chinese medicine and explored its mechanism. Our data showed that Ginsenoside Rb1 (GRb1) can activate TMEM16A directly from the intracellular side in a dose-dependent manner at an EC50of 38.4 ± 2.14 μM. GRb1 specifically activated TMEM16A/B, but not the other previously proposed CaCC mediators such as CFTR and bestrophin. Moreover, GRb1 promoted proliferation of CHO cells stably expressing TMEM16A, in a concentration-dependent manner. Finally, we showed that GRb1 increased the amplitude and frequency of contractions in an isolated guinea pig ileum assay in vivo. In summary, GRb1 can be considered a lead compound for the development of novel drugs for the treatment of diseases caused by TMEM16A dysfunction.
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, 300401, China.|School of Electrical Engineering, Hebei University of Technology, Tianjin, 300401, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Guo
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, 300401, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, 300401, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Pang
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, 300401, China.
authors.forename: Xuzhao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Pharmacology and Toxicology for New Drug, Hebei Province, Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Qi
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, 300401, China.
authors.forename: Li
authors.initials: L
authors.lastname: Mo
authors.affiliation: Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Pharmacology and Toxicology for New Drug, Hebei Province, Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, 300401, China. hailong_an@hebut.edu.cn.
authors.forename: Hailong
authors.initials: H
authors.lastname: An
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, 300401, China. zhany@hebut.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhan
mesh_terms: D000818:Animals; D000075369:Anoctamin-1 / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D036145:Ginsenosides / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D036145:Ginsenosides; C442759:ginsenoside Rb1
keywords: Activator; CaCCs/TMEM16A; Electrophysiology; Ginsenoside Rb1; Ileum contraction