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PDZ Adaptor Protein PDZK2 Stimulates Transport Activity of Organic Cation/Carnitine Transporter OCTN2 by Modulating Cell Surface Expression

Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology (C.W., Y.Ka., Y.Ku., T.S., A.T.) and Department of Histology and Embryology, Graduate School of Medical Science (T.W., S.I.), Kanazawa University, Kakuma, Kanazawa, Japan

A part of the organic cation transporter families (OCT3, OCTN1, and OCTN2) has recently been identified to physically interact with PDZ (PSD95, Dlg, and ZO1) domain-containing proteins, although the physiological relevance of such interaction has not yet been fully examined. Here we have examined the stimulatory effect of PDZK2 [also named NaPi-Cap2 and intestinal and kidney-enriched PDZ protein (IKEPP)] on those cation transporters. In HEK293 cells, coexpression with PDZK2 increased the uptake of carnitine by OCTN2 with minimal effect on its substrate recognition specificity, but not for transport activity of OCT3 or OCTN1. The stimulatory effect of PDZK2 on OCTN2 was compatible with an approximately 2 times increase in transport capacity and can be accounted for by the increase in cell surface expression of OCTN2. Coexpression of PDZK2 did not affect carnitine transport activity of OCTN2 with deletion of the last four amino acids, which were found to be important for the interaction, suggesting involvement of physical interaction of the two proteins in the increase of cell surface expression of OCTN2. In mouse kidney, colocalization of PDZK2 and OCTN2 occurred predominantly in the region that was close to, but not the same as, the surface of apical membranes where OCTN2 alone was observed, suggesting the existence of OCTN2 in the subapical compartment that interacts with PDZK2. The present data have thus proposed an "intracellular pool" for OCTN2 that may be relevant to the stabilization of cell surface expression of OCTN2, thereby increasing transport activity for carnitine.