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J. Biol. Chem., Vol. 279, Issue 15, 14610-14618, April 9, 2004

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Impaired Regulatory Volume Decrease in Freshly Isolated Cholangiocytes from Cystic Fibrosis Mice

IMPLICATIONS FOR CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR EFFECT ON POTASSIUM CONDUCTANCE^*

Won Kyoo Cho¶, Vicki J. Siegrist, and Wendy Zinzow||

From the Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine and The Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana 46202, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, and ^||Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599

Various K⁺ and Cl^– channels are important in cell volume regulation and biliary secretion, but the specific role of cystic fibrosis transmembrane conductance regulator in cholangiocyte cell volume regulation is not known. The goal of this research was to study regulatory volume decrease (RVD) in bile duct cell clusters (BDCCs) from normal and cystic fibrosis (CF) mouse livers. Mouse BDCCs without an enclosed lumen were prepared as described (Cho, W. K. (2002) Am. J. Physiol. 283, G1320–G1327). The isotonic solution consisted of HEPES buffer with 40% of the NaCl replaced with isomolar amounts of sucrose, whereas hypotonic solution was the same as isotonic solution without sucrose. The cell volume changes were indirectly assessed by measuring cross-sectional area (CSA) changes of the BDCCs using quantitative videomicroscopy. Exposure to hypotonic solutions increased relative CSAs of normal BDCCs to 1.20 ± 0.01 (mean ± S.E., n = 50) in 10 min, followed by RVD to 1.07 ± 0.01 by 40 min. Hypotonic challenge in CF mouse BDCCs also increased relative CSA to 1.20 ± 0.01 (n = 53) in 10 min but without significant recovery. Coadministration of the K⁺-selective ionophore valinomycin restored RVD in CF mouse BDCCs, suggesting that the impaired RVD was likely from a defect in K⁺ conductance. Moreover, this valinomycin-induced RVD in CF mice was inhibited by 5-nitro-2'-(3-phenylpropylamino)-benzoate, indicating that it is not from nonspecific effects. Neither cAMP nor calcium agonists could reverse the impaired RVD seen in CF cholangiocytes. Our conclusion is that CF mouse cholangiocytes have defective RVD from an impaired K⁺ efflux pathway, which could not be reversed by cAMP nor calcium agonists.

Received for publication, October 20, 2003 , and in revised form, December 26, 2003.

^* Part of this work was presented at the American Association for the Study of Liver Diseases meetings in Dallas, November 1999 and 2001, and published in abstract form ((1999) Hepatology 30, 461A, and (2001) Hepatology 34, 479A). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by an Indiana University biomedical research grant, National Institutes of Health Grants KO8 DK02613 and R03 DK61409, and a cystic fibrosis research grant. The cystic fibrosis mouse colony at the University of North Carolina was supported by National Institutes of Health Grant RO26-CR02. To whom correspondence should be addressed: Indiana University School of Medicine, Roudebush VA Medical Center, Division of GI/Hepatology (111G), 1481 W. 10th St., Indianapolis, IN 46202. Tel.: 317-554-0000 (ext. 4553); Fax: 317-554-0116; E-mail: wkcho{at}iupui.edu.

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