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1 Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA
2 Sucampo Pharmaceuticals,Inc, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: john.cuppoletti{at}uc.edu.
The purpose of this study was to determine the mechanism of action of SPI-0211 (Lubiprostone), a novel bicyclic fatty acid, under development for the treatment of bowel dysfunction. Adult rabbit intestine was shown to contain mRNA for ClC-2 by RT-PCR, Northern analysis, and in situ hybridization. T84 cells grown to confluence on permeable supports were shown to express ClC-2 channel protein in the apical membrane. SPI-0211 increased electrogenic Cl-transport in T84 cells with an EC50 of approximately 18 nM measured by short circuit current (Isc) after permeabilization of the basolateral membrane with nystatin. SPI-0211 effects on Cl- currents were also measured by whole cell patch clamp using a human epithelial kidney cell line (HEK-293) stably transfected with either recombinant human ClC-2 or recombinant human cystic fibrosis transmembrane regulator (CFTR). In these studies, SPI-0211 activated ClC-2 Cl- currents in a concentration-dependent manner, with an EC50 of approximately 17 nM and had no effect in non-transfected HEK-293 cells. SPI-0211 had no effect on CFTR Cl- channel currents measured in CFTR-transfected HEK-293 cells. Activation of ClC-2 by SPI-0211 was independent of PKA. Together, these studies demonstrate that SPI-0211 is a potent activator of ClC-2 Cl- channels and suggest a physiologically relevant role for ClC-2 Cl- channels in intestinal Cl- transport following SPI-0211 administration.
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