Abstract
Mutations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) cause lethal hereditary disease CF that involves extensive destruction and dysfunction of serous epithelium. Possible pharmacological therapy includes correction of defective intracellular processing and abnormal channel gating. In a previous study, we identified five natural coumarin potentiators of ΔF508-CFTR including osthole, imperatorin, isopsoralen, praeruptorin A, and scoparone. The present study was designed to determine the activity of these coumarine compounds on CFTR activity in animal tissues as a primary evaluation of their therapeutic potential. In the present study, we analyzed the affinity of these coumarin potentiators in activating wild-type CFTR and found that they are all potent activators. Osthole showed the highest affinity with Kd values <50 nmol/L as determined by Ussing chamber short-circuit current assay. Stimulation of rat colonic mucosal secretion by osthole was tested by the Ussing chamber short-circuit current assay. Osthole reached maximal activation of colonic Cl− secretion at 5 μmol/L. Stimulation of mouse tracheal mucosal secretion was analyzed by optical measurement of single gland secretion. Fluid secretion rate of tracheal single submucosal gland stimulated by osthole at 10 μmol/L was three-fold more rapid than that in negative control. In both cases the stimulated secretions were fully abolished by CFTRinh-172. In conclusion, the effective stimulation of Cl– and fluid secretion in colonic and tracheal mucosa by osthole suggested the therapeutic potential of natural coumarin compounds for the treatment of CF and other CFTR-related diseases.
Highlights
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a multidomain glycoprotein, belongs to the adenine nucleotide-binding cassette (ABC) transporter family (Kerem et al, 1989), and is the only anion channel of ABC superfamily (He et al, 2008)
We identified a family of natural coumarin compounds that can potentiate Cl– transport through ΔF508CFTR by screening a collection of 386 natural single compounds from Chinese medicinal herbs (Xu et al, 2008)
The five coumarins stimulated wild-type CFTR (wt-CFTR)-mediated I− influx in a concentration-dependent way, with an affinity sequence from higher to lower as: osthole > scoparone > imperatorin > isopsoralen > praeruptorin A (Figure 1B)
Summary
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a multidomain glycoprotein, belongs to the adenine nucleotide-binding cassette (ABC) transporter family (Kerem et al, 1989), and is the only anion channel of ABC superfamily (He et al, 2008). It has been confirmed that CFTR play a vital role in the absorption and secretion of electrolytes and fluid in submucosal glands (Kunzelmann, 1999; Thiagarajah and Verkman, 2003; Riordan, 2008). In some epithelia such as in colon, CFTR may account for the entire apical chloride conductance (Greger, 2000). CFTR may play roles in establishing the low pH in the biosynthetic compartments of the trans-Golgi network and in endosomes (Machen et al, 2001)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
