title: Stimulation effect of wide type CFTR chloride channel by the naturally occurring flavonoid tangeretin.
abstract: Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel expressed in the apical membrane of serous epithelial cells. Both deficiency and overactivation of CFTR may cause fluid and salt secretion related diseases. In the present study, we identified tangeretin from Pericarpium Citri Reticulatae Viride as a CFTR activator using high-throughput screening based on FRT cell-based fluorescence assay. The activation effect of tangeretin on CFTR chloride channel and the possible underlying mechanisms were investigated. Fluorescence quenching tests showed that tangeretin dose- and time-dependently activated CFTR chloride channel, the activity had rapid and reversible characteristics and the activation effect could be completely reversed by the CFTR specific blocker CFTRinh-172. Primary mechanism studies indicated that the activation effect of tangeretin on CFTR chloride channel was FSK dependent as well as had additional effect with FSK and IBMX suggesting that tangeretin activates CFTR by direct interacting with the protein. Ex-vivo tests revealed that tangeretin could accelerate the speed of the submucosal gland fluid secretion. Short-circuit current measurement demonstrated that tangeretin activated rat colonic mucosa chloride current. Thus, CFTR Cl(-) channel is a molecular target of natural compound tangeretin. Tangeretin may have potential use for the treatment of CFTR-related diseases like cystic fibrosis, bronchiectasis and habitual constipation.
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Central Research Laboratory, Jilin University Bethune Second Hospital, Changchun 130041, PR China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sui
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, PR China.
authors.forename: Yaofang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, PR China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, PR China. Electronic address: hyanglnnu@gmail.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, PR China.
authors.forename: Tonghui
authors.initials: T
authors.lastname: Ma
mesh_terms: D000818:Animals; D002460:Cell Line; D065101:Chloride Channel Agonists / Q000737:chemistry*; D003106:Colon / Q000187:drug effects; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists*; D047309:Flavones / Q000737:chemistry*; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar
chemical_list: D065101:Chloride Channel Agonists; D047309:Flavones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C059006:tangeretin
keywords: Activator; CFTR chloride channel; Fluorescence quenching tests; Patch clamp; Short-circuit current; Tangeretin