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J. Biol. Chem., Vol. 279, Issue 26, 27719-27728, June 25, 2004

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A C-terminal Region Dictates the Apical Plasma Membrane Targeting of the Human Sodium-dependent Vitamin C Transporter-1 in Polarized Epithelia^*

Veedamali S. Subramanian¶, Jonathan S. Marchant¶||, Michael J. Boulware||, and Hamid M. Said**

From the Departments of Medicine and Physiology and Biophysics, University of California, Irvine, California 92697, the Veterans Affairs Medical Center, Long Beach, California 90822, and the ^||Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

The human sodium-dependent vitamin C transporter (hSVCT1) mediates sodium-dependent cellular uptake of the essential micronutrient L-ascorbic acid (vitamin C). However, the molecular determinants that control the cell surface expression, subcellular distribution, and dynamics of hSVCT1 remain undefined. To identify molecular determinants involved in hSVCT1 targeting in polarized epithelia, we used live cell imaging approaches to resolve the targeting and trafficking dynamics of hSVCT1 truncation mutants in renal and intestinal cells. Confocal imaging demonstrated that hSVCT1 was expressed at the apical cell surface and video rate measurements revealed hSVCT1 also resided in a heterogeneous population of intracellular organelles with discrete dynamic properties. By progressive truncation of the cytoplasmic C-terminal tail of hSVCT1, we delimited an essential role for an embedded ten amino acid sequence PICPVFKGFS (amino acids 563-572) in defining the physiological targeting of hSVCT1. Intriguingly, this sequence bears significant homology to recently identified apical targeting motifs in two other sodium-dependent transporters, and we suggest this conservation is reflected topologically through the adoption of a -turn confirmation in the cytoplasmic C-tail of each transporter. Our results provide the first direct resolution of functional hSVCT1 expression at the apical cell surface of polarized epithelia and define an apical targeting signal of relevance to transporters of diverse substrate specificity.

Received for publication, January 27, 2004 , and in revised form, April 12, 2004.

^* This work was supported by the Dept. of Veterans Affairs, National Institutes of Health, and Grants DK-56061 (NIDDK) and DK-58057 (to H. M. S.), a National Service Research Award Fellowship Grant DK-63750 (to V. S. S.), and the Minnesota Medical Foundation (to J. S. M.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Videos.

^¶ Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Veterans Affairs Medical Center-151, Long Beach, CA 90822. Tel.: 562-826-5811; Fax: 562-826-5018; E-mail: hmsaid{at}uci.edu.

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