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J. Biol. Chem., Vol. 283, Issue 23, 16235-16247, June 6, 2008

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SLC41A1 Is a Novel Mammalian Mg²⁺ Carrier^*

Martin Kolisek¹², Pierre Launay¹³, Andreas Beck^¶1, Gerhard Sponder^||, Nicolas Serafini, Marcel Brenkus, Elisabeth Maria Froschauer^||, Holger Martens, Andrea Fleig^¶4, and Monika Schweigel^**25

From the Institute of Veterinary-Physiology, FU Berlin, Oertzenweg 19b, D-14163 Berlin, Germany, the INSERM, U699, Equipe Avenir, Paris F-75018, France, the ^¶Laboratory of Cell and Molecular Signalling, Center for Biomedical Research at The Queen's Medical Center, Honolulu, Hawaii 96813, the ^||Max F. Perutz Laboratories, Department of Microbiology and Genetics, University of Vienna, Dr. Bohrgasse 9, A-1030 Vienna, Austria, and the ^**Research Institute for the Biology of Farm Animals (FBN), Department of Nutritional Physiology "Oskar Kellner," Wilhelm-Stahl-Alee 2, D-18196 Dummerstorf, Germany

The molecular biology of mammalian magnesium transporters and their interrelations in cellular magnesium homeostasis are largely unknown. Recently, the mouse SLC41A1 protein was suggested to be a candidate magnesium transporter with channel-like properties when overexpressed in Xenopus laevis oocytes. Here, we demonstrate that human SLC41A1 overexpressed in HEK293 cells forms protein complexes and locates to the plasma membrane without, however, giving rise to any detectable magnesium currents during whole cell patch clamp experiments. Nevertheless, in a strain of Salmonella enterica exhibiting disruption of all three distinct magnesium transport systems (CorA, MgtA, and MgtB), overexpression of human SLC41A1 functionally substitutes these transporters and restores the growth of the mutant bacteria at magnesium concentrations otherwise non-permissive for growth. Thus, we have identified human SLC41A1 as being a bona fide magnesium transporter. Most importantly, overexpressed SLC41A1 provide HEK293 cells with an increased magnesium efflux capacity. With outwardly directed Mg²⁺ gradients, a SLC41A1-dependent reduction of the free intracellular magnesium concentration accompanied by a significant net decrease of the total cellular magnesium concentration could be observed in such cells. SLC41A1 activity is temperature-sensitive but not sensitive to the only known magnesium channel blocker, cobalt(III) hexaammine. Taken together, these data functionally identify SLC41A1 as a mammalian carrier mediating magnesium efflux.

Received for publication, August 30, 2007 , and in revised form, March 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant P01GM078195 (to A. F.). This work was also supported by the Free University Berlin and Protina Pharmazeutische GmbH (to M. K.), and Avenir funding (to P. L.). 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 These authors contributed equally.

² To whom correspondence may be addressed. Tel.: 49-30-83862628; Fax: 49-30-83862610; E-mail: martink{at}zedat.fu-berlin.de.

³ To whom correspondence may be addressed. E-mail: pierre.launay{at}bichat.inserm.fr.

⁴ To whom correspondence may be addressed. E-mail: afleig{at}hawaii.edu.

⁵ To whom correspondence may be addressed. E-mail: mschweigel{at}fbn-dummerstorf.de.

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