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J. Biol. Chem., Vol. 280, Issue 3, 1764-1770, January 21, 2005

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Bile Acids Induce a Cationic Current, Depolarizing Pancreatic Acinar Cells and Increasing the Intracellular Na⁺ Concentration^*

Svetlana G. Voronina, Olexyi V. Gryshchenko, Oleg V. Gerasimenko, Anne K. Green¶, Ole H. Petersen, and Alexei V. Tepikin||

From the Physiological Laboratory, University of Liverpool, Liverpool L69 3BX, United Kingdom

Biliary disease is a major cause of acute pancreatitis. In this study we investigated the electrophysiological effects of bile acids on pancreatic acinar cells. In perforated patch clamp experiments we found that taurolithocholic acid 3-sulfate depolarized pancreatic acinar cells. At low bile acid concentrations this occurred without rise in the cytosolic calcium concentration. Measurements of the intracellular Na⁺ concentration with the fluorescent probe Sodium Green revealed a substantial increase upon application of the bile acid. We found that bile acids induce Ca²⁺-dependent and Ca²⁺-independent components of the Na⁺ concentration increase. The Ca²⁺-independent component was resolved in conditions when the cytosolic Ca²⁺ level was buffered with a high concentration of the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). The Ca²⁺-dependent component of intracellular Na⁺ increase was clearly seen during stimulation with the calcium-releasing agonist acetylcholine. During acetylcholine-induced Ca²⁺ oscillations the recovery of cytosolic Na⁺ was much slower than the recovery of Ca²⁺, creating a possibility for the summation of Na⁺ transients. The bile-induced Ca²⁺-independent current was found to be carried primarily by Na⁺ and K⁺, with only small Ca²⁺ and Cl^– contributions. Measurable activation of such a cationic current could be produced by a very low concentration of taurolithocholic acid 3-sulfate (10 µM). This bile acid induced a cationic current even when applied in sodium- and bicarbonate-free solution. Other bile acids, taurochenodeoxycholic acid, taurocholic acid, and bile itself also induced cationic currents. Bile-induced depolarization of acinar cells should have a profound effect on acinar fluid secretion and, consequently, on transport of secreted zymogens.

Received for publication, September 7, 2004 , and in revised form, November 8, 2004.

^* This work was supported by a Medical Research Council (MRC) program grant (to O. H. P., O. V. Gerasimenko, and A. V. T.) and an MRC Professorship (to O. H. P.). 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.

These authors have made equal contributions to this study.

Current address: Dept. of Physiology of the Nervous System, Bogomoletz Institute of Physiology, Bogomoletz Street 4, Kiev-24, GSP 01024,Ukraine.

^¶ Current address: BioMedical Research Institute, Dept. of Biological Sciences, The University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.

^|| To whom correspondence should be addressed. Tel.: 44-151-794-53-51; Fax: 44-0-151-794-53-27; E-mail: a.tepikin{at}liv.ac.uk.

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