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Modulation of Renal Apical Organic Anion Transporter 4 Function by Two PDZ Domain–Containing Proteins

Hiroki Miyazaki^*,, Naohiko Anzai^*, Sophapun Ekaratanawong^*, Takeshi Sakata^*, Ho Jung Shin^*, Promsuk Jutabha^*, Taku Hirata^*, Xin He^*, Hiroshi Nonoguchi, Kimio Tomita, Yoshikatsu Kanai^* and Hitoshi Endou^*

^* Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka-shi, Tokyo, Japan; and Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto-shi, Kumamoto, Japan

Address correspondence to: Dr. Yoshikatsu Kanai, Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. Phone: +81-422-47-5511; Fax: +81-422-79-1321; E-mail: ykanai{at}kyorin-u.ac.jp

Received for publication March 22, 2005. Accepted for publication September 1, 2005.

Human organic anion transporter 4 (OAT4) is an apical organic anion/dicarboxylate exchanger in the renal proximal tubules and mediates high-affinity transport of steroid sulfates such as estrone-3-sulfate (E₁S) and dehydroepiandrosterone sulfate. Here, two multivalent PDZ (PSD-95/Discs Large/ZO-1) proteins PDZK1 and NHERF1 were examined as interactors of OAT4 by a yeast two-hybrid assay. These interactions require the extreme C-terminal region of OAT4 and the first and fourth PDZ domains of PDZK1 and the first PDZ domain of NHERF1. These interactions were confirmed by surface plasmon resonance assays (K_D: 36 nM, 1.2 µM, and 41.7 µM, respectively). In vitro binding assays and co-immunoprecipitation studies revealed that the OAT4 wild-type but not a mutant lacking the PDZ motif interacted directly with both PDZK1 and NHERF1. OAT4, PDZK1, and NHERF1 proteins were shown to be localized at the apical membrane of renal proximal tubules. The association with PDZK1 or NHERF1 enhanced OAT4-mediated E₁S transport activities in HEK293 cells (1.2- to 1.4-fold), and the deletion of the OAT4 C-terminal PDZ motif abolished this effect. The augmentation of the transport activity was accompanied by alteration in V_max of E₁S transport via OAT4 and was associated with the increased surface expression level of OAT4 protein. This study indicates that the functional activity of OAT4 is modulated through the PDZ interaction with the network of PDZK1 and NHERF1 and suggests that OAT4 is involved in the regulated apical organic anion handling in the renal proximal tubules, provided by the PDZ scaffold.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673