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The Endogenous CXXC Motif Governs the Cadmium Sensitivity of the Renal Na⁺/Glucose Co-Transporter

Xiaobing Xia^*,, Gang Wang^*, Yanchun Peng, Ming-Gene Tu^,,||, Jimmy Jen and Hongqing Fang^¶

^* Beijing 302 Hospital, Beijing, China; Medical Sciences Division, University of Oxford, Headington, Oxford, United Kingdom; School of Dentistry, China Medical University, Department of Dentistry, China Medical University Hospital, and ^|| Graduate Institute of Dental Sciences, Kaohsiung Medical University, Taiwan; and ^¶ Beijing Institute of Biotechnology, Beijing, China

Address correspondence to: Dr. Xiaobing Xia, Beijing 302 Hospital, Beijing, People’s Republic of China 100039. Phone: 86-10-63801282; Fax: 86-10-83801283; E-mail: xiaobingmpi{at}yahoo.com

Received for publication July 23, 2004. Accepted for publication February 20, 2005.

Cadmium (Cd²⁺) poisoning causes severe renal disorders manifested by defects in reabsorptive transport of various compounds. It is reported here that the renal brush-border membrane Na⁺/glucose co-transporter-1 (SGLT1) is a molecular target for Cd²⁺ toxicity. In micromolar concentrations, Cd²⁺ acted as a noncompetitive, partial inhibitor of methyl-d-glucopyranoside uptake in vesicles from COS-7 cells transiently expressing SGLT1. In contrast, only a modest effect in the closely related Na⁺/myo-inositol co-transporter-1 (SMIT1) was observed. The factor responsible for this difference was the CXXC motif (X can be any residue) at the cytoplasmic end of the eighth transmembrane segment (TM8) of SGLT1. Thus, a mutational transfer of this motif conveyed Cd²⁺ sensitivity to SMIT1. Moreover, mimicking the inhibitory effect of Cd²⁺, the biarsenical molecule FlAsH-EDT₂ strongly inhibited the SGLT1 that had an engineered tetracysteine motif at the cytoplasmic end of TM8. The experiments also showed that covalent binding of the sulfhydryl reactive biotin-PEO-maleimide to the SGLT1 wild type but not to the mutant lacking the CXXC motif was suppressed by Cd²⁺. Taken together, these results suggest that in SGLT1, Cd²⁺ binding to the CXXC motif induces conformational changes that cause a partial inhibition of d-glucose transport.

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