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TRANSLATIONAL PHYSIOLOGY
1Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267-0576; and 2Sucampo Pharmaceuticals, Inc., Bethesda, Maryland 20814
Submitted 26 November 2003 ; accepted in final form 21 June 2004
ABSTRACT
The purpose of this study was to determine the mechanism of action of SPI-0211 (lubiprostone), a novel bicyclic fatty acid in development for the treatment of bowel dysfunction. Adult rabbit intestine was shown to contain mRNA for ClC-2 using RT-PCR, Northern blot 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 across the apical membrane of T84 cells, with an EC50 of 
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 the human embryonic kidney (HEK)-293 cell line 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 17 nM, and had no effect in nontransfected HEK-293 cells. In contrast, 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 after SPI-0211 administration.
cystic fibrosis transmembrane regulator; intestinal chloride channels; chloride channel opener
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