Abstract
Lubiprostone, a 20-carbon synthetic fatty acid used for the treatment of constipation, is thought to act through an action on Cl− channel ClC-2. Short chain fatty acids (SCFAs) are produced and absorbed in the distal intestine. We explore whether SCFAs affect ClC-2, re-examine a possible direct effect of lubiprostone on ClC-2, and use mice deficient in ClC-2 to stringently address the hypothesis that the epithelial effect of lubiprostone targets this anion channel. Patch-clamp whole cell recordings of ClC-2 expressed in mammalian cells are used to assay SCFA and lubiprostone effects. Using chamber measurements of ion current in mice deficient in ClC-2 or CFTR channels served to analyze the target of lubiprostone in the distal intestinal epithelium. Intracellular SCFAs had a dual action on ClC-2, partially inhibiting conduction but, importantly, facilitating the voltage activation of ClC-2. Intra- or extracellular lubiprostone had no effect on ClC-2 currents. Lubiprostone elicited a secretory current across colonic epithelia that was increased in mice deficient in ClC-2, consistent with the channel’s proposed proabsorptive function, but absent from those deficient in CFTR. Whilst SCFAs might exert a physiological effect on ClC-2 as part of their known proabsorptive effect, ClC-2 plays no part in the lubiprostone intestinal effect that appears mediated by CFTR activation.
Highlights
Knowledge of how to manipulate pharmacologically intestinal transport processes is important for the rational design of drugs to combat the intestine’s disorders that can result in diarrheal disease or constipation
An example is cystic fibrosis (CF), an inherited disease caused by mutations that impair the function of CFTR, a Cl− channel important in respiratory as well as intestinal fluid secretion
In view of the results described above, it is difficult to envisage that the activation of intestinal ClC-2 channels by lubiprostone could be the mechanism for its action as a drug to antagonize constipation, but the reality is quite the contrary
Summary
Knowledge of how to manipulate pharmacologically intestinal transport processes is important for the rational design of drugs to combat the intestine’s disorders that can result in diarrheal disease or constipation. An example is cystic fibrosis (CF), an inherited disease caused by mutations that impair the function of CFTR, a Cl− channel important in respiratory as well as intestinal fluid secretion. The search for drugs that target specific defects in the CFTR Cl− channel protein has resulted in the discovery of modulators useful in the treatment of the disease [1,2]. Lubiprostone was proposed to act by promoting intestinal electrolyte and fluid secretion through the activation of Cl− channel ClC-2 [4], but this mechanism has been disputed [5].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
