Received for publication December 28, 2007.
Revised February 25, 2008.
Accepted for publication February 26, 2008.

PDZK1 REGULATES TWO INTESTINAL SOLUTE CARRIERS (Slc15a1 and Slc22a5) IN MICE

Abstract

Gastrointestinal absorption of certain therapeutic agents is thought to be mediated by solute carrier (SLC) transporters, though minimal in vivo evidence has been reported. Here, we demonstrate key roles of PDZ domain-containing protein, PDZK1, as a regulatory mechanism of two solute carriers, Slc15a1 (oligopeptide transporter PEPT1) and Slc22a5 (carnitine/organic cation transporter OCTN2) in mouse small intestine by using pdzk1 gene knockout (pdzk1^-/-) mice. Gastrointestinal absorption of cephalexin, a substrate of PEPT1, after oral administration was delayed in pdzk1^-/- mice compared with wild-type mice. Absorption of carnitine, a substrate of OCTN2 was also decreased in pdzk1^-/- mice. Immunohistochemical analysis revealed the localization of both PEPT1 and OCTN2 at apical membrane of small intestinal epithelial cells in wild-type mice, whereas such apical localization was reduced in pdzk1^-/- mice, with a concomitant decrease in their protein levels assessed by Western blotting in intestinal brush-border membranes. Electron microscopy revealed localization of PEPT1 in intracellular vesicular structures in pdzk1^-/- mice. In addition, we first identified interaction between PEPT1 and PDZK1 in mouse small intestine, and found that PDZK1 stimulates transport activity of PEPT1 by increasing its expression level in HEK293 cells. Taken together, the present findings provide direct evidence that PDZK1 regulates two intestinal SLC transporters in vivo as an adaptor protein for these transporters, and affects oral absorption of their substrates. These findings also raise the possibility that intestinal absorption of the substrate drugs for PEPT1 and OCTN2 is governed by protein network of these transporters and their adaptor PDZK1.

Key words: absorption, drug absorption, intestinal transport, membrane transport, oral absorption, organic cation transport, protein-protein interactions, transporters

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