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¹ Department of Pathology and Laboratory Medicine, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104
² Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104

Address correspondence to Irena Levitan, Department of Pathology and Laboratory Medicine, Institute for Medicine and Engineering, 3340 Smith Walk Philadelphia, PA 19104. Fax: (215) 573-7227; email: ilevitan{at}mail.med.upenn.edu

Depletion of membrane cholesterol and substitution of endogenous cholesterol with its structural analogues was used to analyze the mechanism by which cholesterol regulates volume-regulated anion current (VRAC) in endothelial cells. Depletion of membrane cholesterol enhanced the development of VRAC activated in a swelling-independent way by dialyzing the cells either with GTPS or with low ionic strength solution. Using MßCD–sterol complexes, 50–80% of endogenous cholesterol was substituted with a specific analogue, as verified by gas-liquid chromatography. The effects of cholesterol depletion were reversed by the substitution of endogenous cholesterol with its chiral analogue, epicholesterol, or with a plant sterol, ß-sitosterol, two analogues that mimic the effect of cholesterol on the physical properties of the membrane bilayer. Alternatively, when cholesterol was substituted with coprostanol that has only minimal effect on the membrane physical properties it resulted in VRAC enhancement, similar to cholesterol depletion. In summary, our data show that these channels do not discriminate between the two chiral analogues of cholesterol, as well as between the two cholesterols and ß-sitosterol, but discriminate between cholesterol and coprostanol. These observations suggest that endothelial VRAC is regulated by the physical properties of the membrane.

Key Words: Cl^- channels • cholesterol analogues • physical properties of the membrane • cell swelling • vascular endothelial cells

Abbreviations used in this paper: BAEC, bovine aortic endothelial cell; GTPS, guanosine 5'-O-(3-thiotriphosphate); MßCD, methyl-ß-cyclodextrin; VRAC, volume-regulated anion current; _i, intracellular ionic strength.

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