SLC41A1 Is a Novel Mammalian Mg2+ Carrier

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. 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. Intracellular magnesium, especially its ionized fraction (Mg2+), plays a critical role in enzyme activation, making the ion essential for numerous metabolic processes (1Cowan J.A. Biometals. 2002; 15: 225-235Crossref PubMed Scopus (295) Google Scholar). Mg2+ is an important co-factor in a number of other physiological functions, including the synthesis of biomacromolecules, secretion of hormones, and modulation of ion channel activity (2Hartwig A. Mutat. Res. 2001; 475: 113-121Crossref PubMed Scopus (465) Google Scholar, 3Bara M. Guiet-Bara A. Magn. Res. 2001; 14: 11-18PubMed Google Scholar). It is therefore not surprising that an abnormal Mg2+ homeostasis is associated with several disease conditions, such as cardiovascular diseases, essential hypertension, diabetes mellitus, and metabolic syndrome (4Kisters K. Tokmak F. Kosch M. Dietl K.H. Westermann G. Int. J. Angiol. 1999; 8: 154-156Crossref PubMed Scopus (2) Google Scholar, 5Saris N.E. Mervaala E. Karppanen H. Khawaja J.A. Lewenstam A. Clin. Chim. Acta. 2000; 294: 1-26Crossref PubMed Scopus (1098) Google Scholar, 6Barbagallo, M., Dominguez, L. J., Brucato, V., Galioto, A., Pineo, A., Ferlisi, A., Tranchino, E., Belvedere, M., Putignano, E., and Costanza, G. (2007) in New Perspectives in Magnesium Research (Nishizawa, Y., Morii, H., and Durlach, J., eds) pp. 213-23, Springer-Verlag, LondonGoogle Scholar). However, a better understanding of cellular Mg2+ transport mechanisms and regulation is needed to elucidate the exact role of Mg2+ in these disease processes; at present, this is hampered by limited knowledge of the molecular fundament of the mammalian Mg2+ transport network. Despite extensive evidence for the existence of various regulated Mg2+ transport proteins (7Quamme G.A. Rabkin S.W. Biochem. Biophys. Res. Commun. 1990; 167: 1406-1412Crossref PubMed Scopus (82) Google Scholar, 8Ödblom M.P. Handy R.D. Biochem. Biophys. Res. Commun. 1999; 264: 334-337Crossref PubMed Scopus (11) Google Scholar, 9Schweigel M. Vormann J. Martens H. Am. J. Physiol. 2000; 278: G400-G408Crossref PubMed Google Scholar, 10Schweigel M. Park H.S. Etschmann B. Martens H. Am. J. Physiol. 2006; 290: G56-G65Crossref PubMed Scopus (32) Google Scholar), only two plasma-membrane localized proteins have been identified at the molecular level, namely, TRPM6 and TRPM7, which are ion channels of the melastatin-related transient receptor potential family, and MRS2, a channel located in the inner mitochondrial membrane (11Chubanov V. Gudermann T. Schlingmann K.P. Pflugers Arch. 2005; 451: 228-234Crossref PubMed Scopus (85) Google Scholar, 12Schmitz C. Perraud A.L. Johnson C.O. Inabe K. Smith M.K. Penner R. Kurosaki T. Fleig A. Scharenberg A.M. Cell. 2003; 114: 191-200Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar, 13Kolisek M. Zsurka G. Samaj J. Weghuber J. Schweyen R.J. Schweigel M. EMBO J. 2003; 22: 1235-1244Crossref PubMed Scopus (169) Google Scholar). Thus, the recent description of novel putative Mg2+ transporters, such as the A1 and A2 members of the solute carrier family 41 (SLC41) (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar, A. G.A. Physiol. 2005; PubMed Scopus Google Scholar, A. G.A. Biochem. Biophys. Res. Commun. 2005; PubMed Scopus Google Scholar, J. B. Scharenberg A.M. Biochem. J. 2006; Scopus Google Scholar), the protein H.S. Scopus Google Scholar, A. G.A. Physiol. 2005; 22: PubMed Scopus Google Scholar), a protein magnesium transporter A. G.A. 2005; PubMed Scopus Google and the protein A. R. A. G.A. J. Full Text Full Text PDF PubMed Scopus Google Scholar), have the of cellular Mg2+ transport The proteins and with the protein a novel and family the which of proteins in the transport of various and A. H. Arch. J. Physiol. PubMed Scopus Google data SLC41A1 was identified and by (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar). SLC41A1 been to and a protein of with a molecular of (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar). and the SLC41A1 have been in in and (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar, A. G.A. Physiol. 2005; PubMed Scopus Google Scholar). of the have been identified in and role of SLC41A1 in Mg2+ cellular transport of its to the Mg2+ transporter (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar, J. Smith J. PubMed Google Scholar, J. PubMed Google Scholar). that a Mg2+ increased of SLC41A1 in the and A. G.A. Physiol. 2005; PubMed Scopus Google Scholar). of SLC41A1 to be an cell membrane protein However, the only evidence for SLC41A1 being an Mg2+ transporter been by and A. G.A. Physiol. 2005; PubMed Scopus Google Scholar). a clamp cobalt(III) intracellular total cobalt(III) intracellular total the that of mouse SLC41A1 in Xenopus laevis currents by this we have identified SLC41A1 as an Mg2+ carrier with the to protein that SLC41A1 a temperature-sensitive transport of Mg2+ importantly, that is to Mg2+ transporters MgtA, and at a in data that SLC41A1 is an Mg2+ carrier a significant role in Mg2+ transport by in cellular Mg2+ and by M. E. was by the was by by and and The and Salmonella strain J. PubMed Google Scholar). not otherwise was by of to the growth was to the The and for to and J. Full Text PDF PubMed Google Scholar), that was of the with and in with Mg2+ with to an of and as in bacteria for growth in with to an of and proteins of the as of the membrane fraction the was the membrane protein fraction with a by and with and was the with the of and in with with and to a of bacteria in of and of and the to total magnesium The to protein and data to M. F. Schweigel M. Schweyen R.J. Google the was at a concentration of and the was with by of at in bacteria was a of the with an The in was HEK293 cells with the for for of the cells in and overexpression was with as in C. Perraud A.L. Johnson C.O. Inabe K. Smith M.K. Penner R. Kurosaki T. Fleig A. Scharenberg A.M. Cell. 2003; 114: 191-200Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar). in with and and cells cells for at in and protein fraction was the cell with total proteins and membrane fraction proteins been by to and with to with to to The by by and to The membrane was with and by membrane proteins cells by of the protein with and for in a at with being the to the of M. B. 2006; Scholar). complexes with SLC41A1 by and with The in with for and with and and was by a was cells and for overexpression was with of and cells with at was with cells in at at with for in and with for with the and with the with with of and a was the cell patch clamp at with an with as in C. 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Full Text PDF PubMed Scopus Google of for the was for and at the of by was by the of in the of was by of to all Mg2+ the data data at the of the and The was as the of the of the Thus, for the of any data not otherwise data are as The was the as that for the of with the with The for was in with and the by the of a of was for the The and cells to with HEK293 by and in HEK293 to a cell of cells The of the cells was cells in the HEK293 for to the of Mg2+ to a of the cells in the of Mg2+ at in for three with and with of and of and the to total magnesium in the by was by was to be and cobalt(III) was the molecular of SLC41A1 and its role in cellular Mg2+ we of the in the HEK293 cell was for this of the of overexpression and the of molecular and of SLC41A1 to be an cell membrane protein with putative and and located (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar, A. G.A. Physiol. 2005; PubMed Scopus Google and overexpressed was to the plasma membrane of the HEK293 we several and of the membrane protein fraction and in the SLC41A1 protein was in the plasma membrane of cells by was by of the of with the of to The is known to and the plasma a of and was in cells data by of membrane protein and protein and cells. The to was in the membrane fraction with in the of membrane and protein fraction the was not in cells. Taken together, these data demonstrate the plasma membrane of when overexpressed in HEK293 cells of solute transporters have been to transient protein which are for to be J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, V. M. H. M. Gudermann T. A. PubMed Scopus Google Scholar). such complexes with other we with proteins cells. complexes with and identified two complexes and with molecular and the complexes by in a to concentrations to of we to the of and and the to the molecular of the SLC41A1 of the of and as the of and The of the and complexes by of and complexes not of the limited of the molecular protein complexes in the the of SLC41A1 in and complexes was by SLC41A1 of and Mg2+ of Salmonella with the (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar, A. G.A. Physiol. 2005; PubMed Scopus Google Scholar). been identified in various bacteria J. Smith J. PubMed Google Scholar, J. PubMed Google Scholar), but not in Salmonella its to growth of the strain of Smith and J. PubMed Google have the of in Mg2+ disruption of and the three Mg2+ systems of with that at of this strain to to J. PubMed Google Scholar, M. B. 2006; Scholar). the of to the of strain by with The of of to was by of the total protein as as of the the membrane protein fraction for and in The growth of and at of the growth of strain was in with the growth of strain The growth of strain of the growth of strain when at an of and when at an of not in with an of in of the of at to the of the growth we the of bacteria and by M. F. Schweigel M. Schweyen R.J. Google Scholar). bacteria in Mg2+ and the was The are in The in was and in and and bacteria an and of was observed the of the to of was in strain The data are in with by With this the of the total magnesium concentration for bacteria at an of and at an of was for all three The for was to the in The at and was the for and of and A. G.A. Physiol. 2005; PubMed Scopus Google observed Mg2+ currents associated with mouse SLC41A1 when overexpressed in laevis oocytes. we Mg2+ currents to overexpression in HEK293 cells. such patch clamp in the whole cell with and cells that to a potential of currents at and currents at directed Mg2+ concentration was by of cells with not the these conditions, of a but at membrane to be in SLC41A1 cells that not be in cells. be to have a potential and be by SLC41A1 cells a outwardly was of the and its a with a potential of The of the could be in the of intracellular Mg2+ and the could Mg2+ cells in the and when the its an of Mg2+ was for a significant and the of the at the of the was not with the not these that the not rise to an Mg2+ but of a to the this we the to an with of the channel in a and of the and with the of not the of we of these we an that could not be when was for of cells not and a of the as for by the not a was for a this in a reduction of the during the the not The of a of the not data in with the of the the of channels are by protein J. Google Scholar, K. C. J. Physiol. PubMed Scopus Google we to the be this we and cells with a intracellular with a for rise to a that was to the and in cells in the of this not of any currents in cells and and the currents in an in the of intracellular and Mg2+ not of the any Mg2+ that have been by the currents that in cells. However, of the currents by the with and the cells with an Mg2+ Mg2+ could be It is known that two of Mg2+ L. Johnson E. A. Biophys. PubMed Scopus Google Scholar). any HEK293 cells for in with and in whole cell patch clamp experiments. to that in SLC41A1 HEK293 cells was in cells in not of in HEK293 by of of the of SLC41A1 to the Mg2+ transporter we this protein be in Mg2+ transport as a carrier protein an ion channel therefore to intracellular Mg2+ concentrations by a HEK293 cells SLC41A1 for with the was a in with an of The cells in experiments. of in and cells are in at the of the are for all of and cells and HEK293 cells at various in a The of cells in to a significant decrease of their with that of cells and and The of cells a decrease of their during the to 41 and and of a was in cells HEK293 which a these surprising to an increased efflux of HEK293 cells with the conditions, observed in and cells in and However, and cells a at the of the cells at all was in the of by of that overexpression the to of the free The at the of the to a of the was in and HEK293 cells. The are in that the of HEK293 cells was not that in cells. the patch clamp data an of the in cells with and we this their in this was not the and the of cells with the was not that of cells. the was the in a for this a was in cells was to SLC41A1 overexpression and its was and the of It an of when to but a of was observed and with of The observed the the in at during the of the increased the of SLC41A1 cells when with that observed in cells. to in the Mg2+ that to and when cells conditions, we to the observed accompanied by net of by these all cells in for was for and in the and in the of Mg2+ a of in the of cells was not by in However, when cells in their by with that of cells the such are only by an increased Mg2+ efflux these cells. Mg2+ was during the the of these cells increased by of the intracellular Mg2+ by The observed an of the to we of the Mg2+ to a decrease of in cells. the in Mg2+ to by and of the Mg2+ however, in an and of the Mg2+ the of and Mg2+ and transport we the only known of Mg2+ transport M. Zsurka G. Samaj J. Weghuber J. Schweyen R.J. Schweigel M. EMBO J. 2003; 22: 1235-1244Crossref PubMed Scopus (169) Google Scholar, J. 2000; Full Text Full Text PDF PubMed Scopus Google cobalt(III) the of cells in significant of was in However, in with the of cells was by and with that in cells. Thus, a was in the of Mg2+ only and to at in of the of for and cells in Mg2+ cells in Mg2+ significant the but the to a significant reduction of in Mg2+ the was not by data the existence of a Mg2+ not to SLC41A1 in HEK293 cells. candidate for such a transport is the ion which is in this cell Inabe K. Perraud A.L. Kurosaki T. Penner R. Scharenberg A.M. Fleig A. 2001; Scopus Google Scholar). the of we patch clamp in the whole cell with cells C. Perraud A.L. Johnson C.O. Inabe K. Smith M.K. Penner R. Kurosaki T. Fleig A. Scharenberg A.M. Cell. 2003; 114: 191-200Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar). was the of the when currents at currents to Mg2+ by currents to ion in the of present, understanding of the molecular and cellular of SLC41A1 is The SLC41A1 and the putative Mg2+ transporter (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google and the of SLC41A1 in to a Mg2+ A. G.A. Physiol. 2005; PubMed Scopus Google to the that SLC41A1 is in Mg2+ homeostasis Mg2+ transport in cells of is by data the of MgtA, and Mg2+ transporters by in the Salmonella strain the provide evidence that the Mg2+ carrier in Mg2+ efflux. The for this is overexpression of SLC41A1 in HEK293 cells not detectable in SLC41A1 overexpression to a significant reduction of and the of the Mg2+ the and the number of SLC41A1 in the cell and are temperature-sensitive but not by the Mg2+ channel of the in enterica Salmonella strain with a for the of the candidate Mg2+ transporters to its growth and to identify the of these transporters in Mg2+ transport J. PubMed Google Scholar, J. PubMed Google Scholar, E. J. PubMed Google Scholar). SLC41A1 only been identified in the of (14Wabakken T. E. M. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar, A. G.A. Physiol. 2005; PubMed Scopus Google Scholar), however, to its with the we that be to the of the Mg2+ in bacteria but to the other known Mg2+ transporters as not the which is for members of the of Mg2+ transporters M. Zsurka G. Samaj J. Weghuber J. Schweyen R.J. Schweigel M. EMBO J. 2003; 22: 1235-1244Crossref PubMed Scopus (169) Google Scholar). Nevertheless, as data when overexpressed in the restores the growth of this disruption of Salmonella in Mg2+ However, the of SLC41A1 is that of M. Zsurka G. Samaj J. Weghuber J. Schweyen R.J. Schweigel M. EMBO J. 2003; 22: 1235-1244Crossref PubMed Scopus (169) Google Scholar). The is in the of the and a of the Mg2+ channel by SLC41A1 to data by a significant of the total magnesium concentration in the strain with in with the in the strain with The of to the of Salmonella strain as being a bona fide Mg2+ transporter. in a that its when in Salmonella and that the Salmonella as a a in this However, various solute transporters have been to transient protein complexes to in their systems J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, V. M. H. M. Gudermann T. A. PubMed Scopus Google Scholar). is in with that SLC41A1 forms protein complexes of molecular when overexpressed in HEK293 cells. data the of distinct proteins in the observed SLC41A1 the of SLC41A1 complexes in the mammalian and are for being in such is by recent that all three are being overexpressed in to Mg2+ in J. M. and M. in other protein of the other ion transporters, be in complexes to the observed molecular and and the of the SLC41A1 complexes in to physiological Mg2+ but Mg2+ and with an of in laevis been to various other are A. G.A. Physiol. 2005; PubMed Scopus Google Scholar). and A. G.A. Physiol. 2005; PubMed Scopus Google the Mg2+ However, of the of a for the intracellular ion not the of a Nevertheless, these data that SLC41A1 is an the currents by SLC41A1 overexpression in cells have been identified as by of intracellular Mg2+ and by the transport currents are not by the for Mg2+ the plasma with of the transporter family, been to Mg2+ currents when in laevis A. G.A. 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