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J. Biol. Chem., Vol. 280, Issue 12, 11859-11868, March 25, 2005

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Involvement of c-Src and Protein Kinase C in the Inhibition of Cl^-/OH^- Exchange Activity in Caco-2 Cells by Serotonin^*

Seema Saksena, Ravinder K. Gill, Sangeeta Tyagi, Waddah A. Alrefai, Zaheer Sarwar, Krishnamurthy Ramaswamy, and Pradeep K. Dudeja

From the Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612

Serotonin (5-hydroxytryptamine (5-HT)) is an important neurotransmitter and intercellular messenger regulating various gastrointestinal functions, including electrolyte transport. To date, however, no information is available with respect to its effects on the human intestinal apical anion exchanger Cl^-/OH^- (). The present studies were therefore undertaken to examine the direct effects of serotonin on OH^- gradient-driven 4,4'-diisothiocyanato-stilbene-2, 2'-disulfonic acid-sensitive ³⁶Cl^- uptake utilizing the post-confluent transformed human intestinal epithelial cell line Caco-2. Our results demonstrate that serotonin inhibits Cl^-/OH^- exchange activity in Caco-2 cells via both tyrosine kinase and Ca²⁺-independent protein kinase C-mediated pathways involving either 5-HT3 or 5-HT4 receptor subtype. The data consistent with our inference are as follows. (i) The short term treatment of cells with 5-HT (0.1 µM) for 15-60 min significantly decreased Cl^-/OH^- exchange (50-70%, p < 0.05). (ii) The specific agonists for 5-HT3, m-chlorophenylbiguanide, and 5-HT4, 3-(4-allylpiperazin-1-yl)-2-quinoxaline chloronitrile, mimicked the effects of serotonin. (iii) Tropisetron dual inhibitor for both the 5-HT3/4 receptor subtypes significantly blocked the inhibition, whereas specific 5-HT3 (Y-25130) or 5-HT4 receptor (RS39604) antagonist failed to block the inhibitory effects of 5-HT. (iv) The Ca²⁺ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl ester) had no effect on the serotonin-induced inhibition. (v) The specific protein kinase C (PKC) inhibitors chelerythrine chloride or calphostin C completely blocked the inhibition by 5-HT. (vi) The specific inhibitor for PKC, rottlerin, significantly blocked the inhibition by 5-HT. (vii) The specific tyrosine kinase inhibitor, herbimycin, or Src family kinase inhibitor, PP1, abolished the 5-HT-mediated inhibition of Cl^-/OH^- exchange activity. (viii) 5-HT stimulated tyrosine phosphorylation of c-Src kinase and PKC.

Received for publication, October 12, 2004 , and in revised form, December 22, 2004.

^* This work was supported by the Department of Veterans Affairs and by NIDDK Grants DK 68324 and DK 54016 (to P. K. D.), DK 67990 and DK 33349 (to K. R.), and DK 62221 (to W. A. A.) from the National Institutes of Health. 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.

To whom correspondence and reprint requests should be addressed: University of Illinois, Medical Research Service (600/151), Jesse Brown Veterans Affairs Medical Center, 820 South Damen Ave., Chicago, IL 60612. Tel.: 312-569-7434; Fax: 312-569-6487; E-mail: pkdudeja{at}uic.edu.

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