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J. Biol. Chem., Vol. 282, Issue 36, 26471-26480, September 7, 2007

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Human Copper Transporter hCTR1 Mediates Basolateral Uptake of Copper into Enterocytes

IMPLICATIONS FOR COPPER HOMEOSTASIS^*

From the Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607

Copper is essential for human growth and survival. Enterocytes mediate the absorption of dietary copper from the intestinal lumen into blood as well as utilizing copper for their biosynthetic needs. Currently, the pathways for copper entry into enterocytes remain poorly understood. We demonstrate that the basolateral copper uptake into intestinal cells greatly exceeds the apical uptake. The basolateral but not apical transport is mediated by the high affinity copper transporter hCTR1. This unanticipated conclusion is supported by cell surface biotinylation and confocal microscopy of endogenous hCTR1 in Caco2 cells as well as copper influx measurements that show saturable high affinity uptake at the basolateral but not the apical membrane. Basolateral localization of hCTR1 and polarized copper uptake are also conserved in T84 cells, models for intestinal crypt cells. The lateral localization of hCTR1 seen in intestinal cell lines is recapitulated in immunohistochemical staining of mouse intestinal sections. Biochemical and functional assays reveal the basolateral localization of hCTR1 also in renal Madin-Darby canine kidney cells and opossum kidney cells. Overexpression of hCTR1 in Madin-Darby canine kidney cells results in both apical and basolateral delivery of the overexpressed protein and greatly enhanced copper uptake at both cell surfaces. We propose a model of intestinal copper uptake in which basolateral hCTR1 plays a key role in the physiologically important delivery of copper from blood to intracellular proteins, whereas its role in the initial apical uptake of dietary copper is indirect.

Received for publication, March 28, 2007 , and in revised form, July 9, 2007.

^* These studies were supported by National Institutes of Health Grant P01 GM 067166, Project 1 (to J. H. K.). 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.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, University of Illinois, Molecular Biology Research Building (MC669), 900 S. Ashland Ave., Chicago, IL 60607. Tel.: 312-355-2732; Fax: 312-355-1765; E-mail: kaplanj{at}uic.edu.

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