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J. Biol. Chem., Vol. 279, Issue 52, 54826-54832, December 24, 2004

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Association of Paracellin-1 with ZO-1 Augments the Reabsorption of Divalent Cations in Renal Epithelial Cells^*

Akira Ikari, Naho Hirai, Morihiko Shiroma, Hitoshi Harada, Hideki Sakai¶, Hisayoshi Hayashi||, Yuichi Suzuki||, Masakuni Degawa**, and Kuniaki Takagi

From the Department of Environmental Biochemistry and Toxicology, School of Pharmaceutical Sciences, ^**Department of Molecular Toxicology and the 21st Century COE program, School of Pharmaceutical Sciences, and ^||Laboratory of Physiology, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan and the ^¶Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan

Paracellin-1 (PCLN-1) belongs to the claudin family of tight junction proteins and possibly plays a critical role in the reabsorption of magnesium and calcium. So far, the physiological properties of PCLN-1 have not been clarified. In the present study, we investigated whether PCLN-1 is associated with ZO-1. We also investigated whether ⁴⁵Ca²⁺ transport across the paracellular barrier is affected by this association. In vitro binding analysis using glutathione S-transferase fusion protein showed that the C-terminal TRV sequence, especially Thr and Val residues, of PCLN-1 interacts with ZO-1. Next, PCLN-1 was stably expressed in Madin-Darby canine kidney cells using a FLAG tagging vector. ZO-1 was co-immunoprecipitated with the wild-type PCLN-1 and the alanine substitution (TAV) mutant. However, mutants of the deletion (TRV) and the alanine substitution (ARV and TRA) inhibited the association of PCLN-1 with ZO-1. Confocal immunofluorescence demonstrated that the wild-type PCLN-1 and the TAV mutant localized in the tight junction along with ZO-1, but the TRV, ARV, and TRA mutants were widely distributed in the lateral membrane including the tight junction area. Interestingly, monolayers of cells expressing the wild-type PCLN-1 and the TAV mutant showed higher activities of ⁴⁵Ca²⁺ transport from apical to basal compartments, compared with those expressing the TRV, ARV, and TRA mutants and the mock cells. ⁴⁵Ca²⁺ transport was inhibited by increased magnesium concentration suggesting that magnesium and calcium were competitively transported by PCLN-1. It was noted that a positive electrical potential gradient enhanced ⁴⁵Ca²⁺ transport from apical to basal compartments without affecting the opposite direction of transport. Thus, PCLN-1 localizes to the tight junction followed by association with ZO-1, and the PCLN-1·ZO-1 complex may play an essential role in the reabsorption of divalent cations in renal epithelial cells.

Received for publication, June 7, 2004 , and in revised form, October 15, 2004.

^* This work was supported in part by the grants from the Salt Science Research Foundation, number 0332, and the Takeda Science Foundation (to A. I.). 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 should be addressed: Dept. of Environmental Biochemistry and Toxicology, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Shizuoka 422-8526, Japan. Tel.: 81-54-264-5674; Fax: 81-54-264-5672; E-mail: ikari{at}u-shizuoka-ken.ac.jp.

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